N-[(substituted five-membered di- or triaza diunsaturated ring)carbonyl] guanidine derivatives for the treatment of ischemia

ABSTRACT

NHE-1 inhibitors, methods of using such NHE-1 inhibitors and pharmaceutical compositions containing such NHE-1 inhibitors. The NHE-1 inhibitors are useful for the reduction of tissue damage resulting from tissue ischemia.

This application was filed under 35 U.S.C. §371 based on PCT/IB99/00206which was filed Feb. 5, 1999 which claims priority from U.S. provisionalapplication serial No. 60/076,362 which was filed on Feb. 27, 1998 andis now abandoned.

BACKGROUND OF INVENTION

This invention relates to sodium-hydrogen exchanger type 1 (NHE-1)inhibitors, pharmaceutical compositions containing such inhibitors andthe use of such inhibitors to treat for example, ischemia particularly,perioperative myocardial ischemic injury in mammals, including humans.

Mycardial ischemic injury can occur in out-patient as well as inperioperative settings and can lead to the development of sudden death,myocardial infarction or congestive heart failure. There is an unmetmedical need to prevent or minimize myocardial ischemic injury,particularly perioperative myocardial infarction. Such a therapy isanticipated to be life-saving and reduce hospitalizations, enhancequality of life and reduce overall health care costs of high riskpatients.

Pharmacological cardioprotection would reduce the incidence andprogression of myocardial infarction and dysfunction occurring in thesesurgical settings (perioperatively). In addition to reducing myocardialdamage and improving post-ischemic myocardial function in patients withischemic heart disease, cardioprotection would also decrease theincidence of cardiac morbidity and mortality due to myocardialinfarction and dysfunction in patients “at risk” (such as greater than65 years, exercise intolerant, coronary artery disease, diabetesmellitus, hypertension) that require non-cardiac surgery.

The mechanism(s) responsible for the myocardial injury observed afterischemia and reperfusion is not fully understood.

A variety of publications have disclosed the use of guanidinederivatives as useful for the treatment of, for example arrhythmias.

U.S. Pat. No. 5,698,581, granted Dec. 16, 1997 (EP 676395 A2 published1995), discloses certain substituted N-heteroarylguanidines asinhibitors of the (Na+/H+) exchange transport system useful for thetreatment of, for example, arrhythmias.

EP 803 501 A1, published Oct. 10, 1997, discloses substituted guanidinederivatives useful as (Na+/H+) exchange inhibitors.

WO 94/26709 discloses guanidine derivatives as inhibitors of (Na+/H+)exchange in cells.

PCT/JP97/04650 application published on Jun. 25, 1998 disclosesN-[(substituted five-membered heteroaryl)carbonyl]guanidine compoundswhich are stated to be useful as inhibitors of Na⁺/H⁺ exchange andconsequently effective for the treatment of various diseases such ashypertension, arrhythmia, angina pectoris, myocardial infarct,arteriosclerosis, and complications of diabetes.

Thus, there is clearly a need and a continuing search in this field ofart for treatments for perioperative myocardial ischemia.

SUMMARY OF THE INVENTION

This invention is directed to a compound of Formula I

a prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug wherein

Z is carbon connected and is a five-membered, diaza, diunsaturated ringhaving two contiguous nitrogens, said ring optionally mono-, di-, ortri-substituted with up to three substituents independently selectedfrom R¹, R² and R³;

or

Z is carbon connected and is a five-membered, triaza, diunsaturatedring, said ring optionally mono- or di-substituted with up to twosubstituents independently selected from R⁴ and R⁵;

wherein R¹, R², R³, R⁴ and R⁵ are each independently hydrogen,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl, (C₁-C₄)alkylthio, (C₃-C₄)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl, mono-N-— or di-N,N—(C₁-C₄)alkylcarbamoyl, M or M(C₁-C₄)alkyl, anyof said previous (C₁-C₄)alkyl moieties optionally having from one tonine fluorines; said (C₁-C₄)alkyl or (C₃-C₄)cycloalkyl optionally mono-or di-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alklthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,(C₁-C₄)alkyl, mono-N- or di-N,N—(C₁-C₄)alkylcarbamoyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl; and said (C₃-C₄)cycloalkyl optionallyhaving from one to seven fluorines;

wherein M is a partially saturated, fully saturated or fully unsaturatedfive to eight membered ring optionally having one to three heteroatomsselected independently from oxygen, sulfur and nitrogen, or, a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated three to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

said M is optionally substituted, on one ring if the moiety ismonocyclic, or one or both rings if the moiety is bicyclic, on carbon ornitrogen with up to three substituents independently selected from R⁶,R⁷ and R⁸, wherein one of R⁶, R⁷ and R⁸ is optionally a partiallysaturated, fully saturated, or fully unsaturated three to seven memberedring optionally having one to three heteroatoms selected independentlyfrom oxygen, sulfur and nitrogen optionally substituted with(C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸ are optionally hydroxy,nitro, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino or(C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido;(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄) alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines.

A preferred group of compounds, designated the A group, contains thosecompounds having the Formula I as shown above wherein Z is

R¹ and R³ are each independently hydrogen, (C₁-C₄)alkyl,(C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl, said (C₁-C₄)alkyloptionally substituted with from one to nine fluorines, said R¹ and R³substituents optionally mono- or di-subtituted independently withhydroxy, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl or(C₁-C₄)alkylsulfonyl; and

R² is unsubstituted (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl; or R² is phenyl,phenyl(C₁-C₄)alkyl, pyridyl or pyrimidinyl or a bicyclic ring consistingof two fused five and/or six membered rings taken independentlyoptionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen, said R² substituent optionally mono-, di-or tri-substituted independently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,hydroxy, (C₁-C₄)alkoxycarbonyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl,mono-N— or di-N,N—(C₁-C₄)alkylamino, (C₁-C₄)alkylsulfonyl orsulfonamido, said (C₁-C₄)alkyl or (C₁-C₄)alkoxy optionally substitutedwith from one to nine fluorines or the pharmaceutically acceptable saltsthereof.

A group of compounds which is preferred among the A Group of compoundsdesignated the B Group, contains those compounds wherein

R¹ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl;

R² is phenyl, optionally mono- or di-substituted; and

R³ is hydrogen or the pharmaceutically acceptable salts thereof.

Especially preferred compounds of Formula I are the compounds

[1-(2-chlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidine;

[5-methyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidine;

[5-ethyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine;

[5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidine;

[5-cyclopropyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine;

[5-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]guanidineand the pharmaceutically acceptable salts thereof.

Especially preferred compounds within the B Group of compounds arecompounds wherein

a.

R² is 2-chlorophenyl; and

R¹ is methyl;

b.

R² is 2-trifluoromethylphenyl; and

R¹ is methyl;

c.

R² is phenyl; and

R¹ is ethyl;

d.

R² is 2-trifluoromethylphenyl; and

R¹ is cyclopropyl;

e.

R² is phenyl; and

R¹ is cyclopropyl; and

f.

R² is 2,6-dichlorophenyl; and

R¹ is cyclopropyl or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the A Group of compoundsdesignated the C Group, contains those compounds wherein

R¹ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl;

R² is naphthalenyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanylor benzodioxolyl, said R² substituent optionally mono-substituted; and

R³ is hydrogen or the pharmaceutically acceptable salts thereof.

Especially preferred compounds of Formula I are the compounds

[5-methyl-1-(quinolin-6-yl)-1H-pyrazole-4-carbonyl]guanidine;

[5-methyl-1-(naphthalen-1-yl)-1H-pyrazole-4-carbonyl]guanidine;

[5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine;

[5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidine andthe pharmaceutically acceptable salts thereof.

Especially preferred compounds within the C Group of compounds arecompounds wherein

a.

R² is 1-naphthalenyl; and

R¹ is methyl;

b.

R² is 5-quinolinyl; and

R¹ is cyclopropyl;

c.

R² is 8-quinolinyl; and

R¹ is cyclopropyl; and

d.

R² is 6-quinolinyl; and

R¹ is methyl or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the A Group of compounds,designated the D Group, contains those compounds wherein

R¹ is hydrogen;

R² is phenyl, optionally mono- or di-substituted; and

R³ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl or the pharmaceuticallyacceptable salts thereof.

Especially preferred compounds of Formula I are the compounds

[3-methyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine;

[3-methyl-1-(naphthalen-1-yl)-1H-pyrazole-4-carbonyl]guanidine;

[3-methyl-1-(isoquinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine and thepharmaceutically acceptable salts thereof.

An especially preferred compound within the D Group of compounds is thecompound wherein

R² is phenyl; and

R³ is methyl or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the A Group of compounds,designated the E Group, contains those compounds wherein

R¹ is hydrogen;

R² is naphthalenyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanylor benzodioxolyl, said R² substituent optionally mono-substituted; and

R³ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl or the pharmaceuticallyacceptable salts thereof.

Especially preferred compounds within the E Group of compounds arecompounds wherein

a.

R² is 1-naphthalenyl; and

R³ is methyl; and

b.

R² is 5-isoquinolyl; and

R³ is methyl or the pharmaceutically acceptable salts thereof.

A preferred group of compounds, designated the F Group, contains thosecompounds having the Formula I as shown above wherein Z is

R¹ is hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl orphenyl(C₁-C₄)alkyl, said (C₁-C₄)alkyl optionally substituted with fromone to nine fluorines, said R¹ substituents optionally mono- ordi-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl or (C₁-C₄)alkylsulfonyl; and

R² and R³ are each independently unsubstituted (C₁-C₄)alkyl or(C₃-C₇)cycloalkyl; or R² and R³ are each independently phenyl orphenyl(C₁-C₄)alkyl, pyridyl or pyrimidinyl or a bicyclic ring consistingof two fused five and/or six membered rings taken independentlyoptionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen, said R² and R³ substituents optionallymono-, di- or tri-substituted independently with halo, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, hydroxy, trifluoromethoxy, (C₁-C₄)alkoxycarbonyl, mono-N—or di-N,N—(C₁-C₄)alkylcarbamoyl, mono-N— or di-N,N-C₁-C₄)alkylamino,(C₁-C₄)alkylsulfonyl or sulfonamido, said (C₁-C₄)alkyl or (C₁-C₄)alkoxyoptionally substituted with from one to nine fluorines or thepharmaceutically acceptable salts thereof.

An especially preferred compound of Formula I is

[4-methyl-1-phenyl-1H-pyrazole-3-carbonyl]guanidine and apharmaceutically acceptable salt thereof.

An especially preferred compound within the F Group of compounds is acompound wherein

R³ is phenyl;

R¹ is methyl; and

R² is H or the pharmaceutically acceptable salts thereof.

A preferred group of compounds, designated the G Group, contains thosecompounds having the Formula I as shown above wherein Z is

R¹ and R³ are each independently hydrogen, (C₁-C₄)alkyl,(C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl, said (C₁-C₄)alkyloptionally substituted with from one to nine fluorines, said R¹ and R³substituents optionally mono- or di-substituted independently withhydroxy, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl or(C₁-C₄)alkylsulfonyl; and

R² is unsubstituted (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl; or R² is phenyl,phenyl(C₁-C₄)alkyl, pyridyl or pyrimidinyl or a bicyclic ring consistingof two fused five and/or six membered rings taken independentlyoptionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen, said R² substituent optionally mono-, di-or tri-substituted independently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,hydroxy, (C₁-C₄)alkoxycarbonyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl,mono-N— or di-N,N—C₁-C₄)alkylamino, (C₁-C₄)alkylsulfonyl or sulfonamido,said (C₁-C₄)alkyl or (C₁-C₄)alkoxy optionally substituted with from oneto nine fluorines or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the G Group of compounds,designated the H Group, contains those compounds wherein

R¹ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl;

R² is phenyl, optionally mono- or di-substituted; and

R³ is hydrogen or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the G Group of compounds,designated the I Group, contains those compounds wherein

R¹ is (C₁-C₄)alkyl or (C₃-C₇)cydoalkyl;

R² is naphthalenyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanylor benzodioxolyl, said R² substituent optionally mono-substituted; and

R³ is hydrogen.

A group of compounds which is preferred among the G Group of compounds,designated the J Group, contains those compounds wherein

R¹ is hydrogen;

R² is phenyl, optionally mono- or di-substituted; and

R³ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl.

Especially preferred compounds of Formula I are the compounds

[2-methyl-5-phenyl-2H-pyrazole-3-carbonyl]guanidine;

[2-methyl-5-(naphthalen-1-yl)-2H-pyrazole-3-carbonyl]guanidine and thepharmaceutically acceptable salts thereof.

An especially preferred compound within the J Group of compounds is thecompound wherein

R² is phenyl; and

R³ is methyl or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the G Group of compounds,designated the K Group, contains those compounds wherein

R¹ is hydrogen;

R² is naphthalenyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanylor benzodioxolyl, said R² substituent optionally mono-substituted; and

R³ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl or the pharmaceuticallyacceptable salts thereof.

An especially preferred compound within the K Group of compounds is thecompound wherein

R² is 1-naphthalenyl; and

R³ is methyl and the pharmaceutically acceptable salts thereof.

A preferred group of compounds, designated the L Group, contains those,compounds having the Formula I as shown above wherein Z is

R⁴ is hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl orphenyl(C₁-C₄)alkyl, said (C₁-C₄)alkyl optionally substituted with fromone to nine fluorines, said R⁴ substituent optionally mono- ordi-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl or (C₁C₄)alkylsulfonyl; and

R⁵ is unsubstituted (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl; or R⁵ is phenyl,phenyl(C₁-C₄)alkyl, pyridyl or pyrimidinyl or a bicyclic ring consistingof two fused five and/or six membered rings taken independentlyoptionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen, said R⁵ substituent optionally mono-, di-or tri-substituted independently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,hydroxy, (C₁-C₄)alkoxycarbonyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl,mono-N— or di-N,N—(C₁-C₄)alkylamino, (C₁-C₄)alkylsulfonyl, orsulfonamido, said (C₁-C₄)alkyl or (C₁-C₄)alkoxy optionally substitutedwith from one to nine fluorines or the pharmaceutically acceptable saltsthereof.

A preferred group of compounds, designated the M Group, contains thosecompounds having the Formula I as shown above wherein Z is

R⁴ is hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl,phenyl(C₁-C₄)alkyl, said (C₁-C₄)alkyl optionally substituted with fromone to nine fluorines, said R⁴ substituent optionally mono- ordi-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl or (C₁-C₄)alkylsulfonyl; and

R⁵ is unsubstituted (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl; or R⁵ is phenyl,phenyl(C₁-C₄)alkyl, pyridyl or pyrimidinyl or a bicyclic ring consistingof two fused five and/or six membered rings taken independentlyoptionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen, said R⁵ substituent optionally mono-, di-or tri-substituted independently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,hydroxy, (C₁-C₄)alkoxycarbonyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl,mono-N— or di-N,N—(C₁-C₄)alkylamino, (C₁-C₄)alkylsulfonyl orsulfonamido, said (C₁-C₄)alkyl or (C₁-C₄)alkoxy optionally substitutedwith from one to nine fluorines or the pharmaceutically acceptable saltsthereof.

A preferred group of compounds, designated the N Group, contains thosecompounds having the Formula I as shown above wherein Z is

R⁴ is hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl orphenyl(C₁-C₄)alkyl, said (C₁-C₄)alkyl optionally substituted with fromone to nine fluorines, said R⁴ substituent optionally mono- ordi-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl or (C₁-C₄)alkylsulfonyl; and

R⁵ is unsubstituted (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl; or R⁵ is phenyl,phenyl(C₁-C₄)alkyl, pyridyl or pyrimidinyl or a bicyclic ring consistingof two fused five and/or six membered rings taken independentlyoptionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen, said R⁵ substituent optionally mono-, di-or tri-substituted independently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,hydroxy, (C₁-C₄)alkoxycarbonyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl,mono-N— or di-N,N—(C₁-C₄)alkylamino, (C₁-C₄)alkylsulfonyl orsulfonamido, said (C₁-C₄)alkyl or (C₁-C₄)alkoxy optionally substitutedwith from one to nine fluorines or the pharmaceutically acceptable saltsthereof.

A preferred group of compounds, designated the O Group, contains thosecompounds having the Formula I as shown above wherein Z is

R⁴ is hydrogen, (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl orphenyl(C₁-C₄)alkyl, said (C₁-C₄)alkyl optionally substituted with fromone to nine fluorines, said R⁴ substituent optionally mono- ordi-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl or (C₁-C₄)alkylsulfonyl; and

R⁵ is unsubstituted (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl; or R⁵ is phenyl,phenyl(C₁-C₄)alkyl, pyridyl or pyrimidinyl or a bicyclic ring consistingof two fused five and/or six membered rings taken independentlyoptionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen, said R⁵ substituent optionally mono-, di-or tri-substituted independently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,hydroxy, (C₁-C₄)alkoxycarbonyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl,mono-N— or di-N,N—(C₁-C₄)alkylamino, (C₁-C₄)alkylsulfonyl orsulfonamido, said (C₁-C₄)alkyl or (C₁-C₄)alkoxy optionally substitutedwith from one to nine fluorines or the pharmaceutically acceptable saltsthereof.

A group of compounds which is preferred among the O Group of compoundsdesignated the P Group, contains those compounds wherein

R⁴ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl; and

R⁵ is phenyl, optionally mono- or di-substituted or the pharmaceuticallyacceptable salts thereof.

Especially preferred compounds of Formula I are the compounds

[5-methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl]guanidine;

[5-methyl-2-(3-methoxyphenyl)-2H-1,2,3-triazole-4-carbonyl]guanidine;

[2-(3-bromophenyl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidine andthe pharmaceutically acceptable salts thereof.

Especially preferred compounds within the P Group of compounds arecompounds wherein

a.

R⁵ is phenyl; and

R⁴ is methyl;

b.

R⁵ is 3-methoxyphenyl; and

R⁴ is methyl; and

c.

R⁵ is 3-bromophenyl; and

R⁴ is methyl or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the O Group of compounds,designated the Q Group, contains those compounds wherein

R⁴ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl; and

R⁵ is naphthalenyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanylor benzodioxolyl, said R⁵ substituents optionally mono-substituted orthe pharmaceutically acceptable salts thereof.

Especially preferred compounds of Formula I are the compounds

[2-(naphthalen-1-yl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidine;

[2-(isoquinolin-5-yl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidine;

[5-methyl-2-(quinolin-5-yl)-2H-1,2,3-triazole-4-carbonyl]guanidine andthe pharmaceutically acceptable salts thereof.

Especially preferred compounds within the Q Group of compounds arecompounds wherein

a.

R⁵ is 1-naphthalenyl; and

R⁴ is methyl;

b.

R⁵ is 5-isoquinolinyl; and

R⁴ is methyl; and

c.

R⁵ is 5-quinolinyl; and

R⁴ is methyl or the pharmaceutically acceptable salts thereof.

Another aspect of this invention is directed to the following compounds:

5-Methyl-2-(5-quinolinyl)-2H-1,2,3-triazole-4-carboxylic acid,

5-Methyl-2-(5-isoquinolinyl)-2H-1,2,3-triazole-4-carboxylic acid,

2-(1-Naphthalenyl)-5-methyl-2H-1,2,3-triazole-4-carboxylic acid,

Ethyl5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate,

Ethyl 5-methyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylate,

Ethyl 5-methyl-1-naphthalenyl-1H-pyrazole-4-carboxylate,

Ethyl 5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carboxylate,

Ethyl 5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate,

Methyl 5-ethyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate,

n-Butyl 1-(isoquinolin-5-yl)-3-methyl-1H-pyrazole-4-carboxylate,

5-Methyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylic acid,

5-Methyl-1-naphthalenyl-1H-pyrazole-4-carboxylic acid,

5-Cyctlopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carboxylic acid,

5-Cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carboxylic acid,

5-Ethyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid,

5-Cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid or

1-(Isoquinolin-5-yl)-3-methyl-1H-pyrazole-4-carboxylic acid or apharmaceutically acceptable salt of said compound.

A preferred group of compounds designated the R group, contains thosecompounds having the Formula I as shown above wherein Z is

R¹ is (C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl, said(C₃-C₇)cycloalkyl optionally substituted with from one to threefluorines, said R¹ substituent optionally mono- or di-substitutedindependently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinylor (C₁-C₄)alkylsulfonyl; and

R² is (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, M or M(C₁-C₄)alkyl, any of saidprevious (C₁-C₄)alkyl moieties optionally having from one to ninefluorines; said (C₁-C₄)alkyl or (C₃-C₄)cycloalkyl optionally mono- ordi-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,(C₁-C₄)alkyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl; and said (C₃-C₄)cycloalkyl optionallyhaving from one to seven fluorines;

wherein M is a partially saturated, fully saturated or fully unsaturatedfive to eight membered ring optionally having one to three heteroatomsselected independently from oxygen, sulfur and nitrogen, or, a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated three to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

said M is optionally substituted, on one ring if the moiety ismonocyclic, or one or both rings if the moiety is bicyclic, on carbon ornitrogen with up to three substituents independently selected from R⁶,R⁷ and R⁸, wherein one of R⁶, R⁷ and R⁸ is optionally a partiallysaturated, fully saturated, or fully unsaturated three to seven memberedring optionally having one to three heteroatoms selected independentlyfrom oxygen, sulfur and nitrogen optionally substituted with(C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸ are optionally hydroxy,nitro, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono,N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alitylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino or(C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfon, amido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines or the pharmaceutically acceptable salts thereof.

An especially preferred compound of Formula I is the compound

[1-(Naphthalen-1-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine orthe pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the R Group of compoundsdesignated the S Group, contains those compounds wherein

R¹ is cyclopropyl; and

R² is 1-naphthalenyl or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the R Group of compoundsdesignated the T Group, contains those compounds wherein

R¹ is (C₃-C₇)cycloalkyl; and

R² is a five to six membered monocyclic aromatic ring optionally havingone to two heteroatoms selected independently from oxygen, sulfur andnitrogen;

said R² ring is optionally mono-substituted on carbon or nitrogen with afully saturated or fully unsaturated five to six membered ringoptionally having one to two heteroatoms selected independently fromoxygen, sulfur and nitrogen, said ring optionally mono-substituted with(C₁-C₄)alkyl

said R² ring is also optionally mono- or di-substituted independently oncarbon or nitrogen with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino are optionallymono-substituted with hydroxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoylamino, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino,sulfornamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkylaminosulfonyl oroptionally substituted with one to nine fluorines or thepharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the T Group of compoundsdesignated the U Group, contains those compounds wherein

R¹ is cyclopropyl; and

R² is phenyl, optionally mono- or di-substituted independently withhydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl,(C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl,mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino substituents are optionally mono-substitutedwith hydroxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tofive fluorines;

or the pharmaceutically acceptable salts thereof.

Especially preferred compounds, of Formula I are the compounds

[5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidine;

[5-cyclopropyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine; or

[5-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]guanidine

or the pharmaceutically acceptable salts of said compounds.

Other especially preferred compounds of Formula I are the compounds

[1-(2-Chloro-4-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Trifluoromethyl-4-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Fluorophenyl-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Chloro-5-methoxyphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Chloro-4-methylaminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2,5-Dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2,3-Dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Chloro-5-aminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Chloro-5-aminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Fluoro-6-trifluoromethylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Chloro-5-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Chloro-5-dimethylaminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Trifluoromethyl-4-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guahidine;

or pharmaceutically acceptable salts of said compounds.

Especially preferred compounds within the U Group are compounds wherein

a. R² is 2-chloro-4-methylsulfonylphenyl;

b. R² is 2-chlorophenyl;

c. R² is 2-trifluoromethyl-4-fluorophenyl;

d. R² is 2-bromophenyl;

e. R² is 2-fluorophenyl;

f. R² is 2-chloro-5-methoxyphenyl;

g. R² is 2-chloro-4-methylaminosulfonylphenyl;

h. R² is 2,5-dichlorophenyl;

i. R² is 2,3-dichlorophenyl;

j. R² is 2-chloro-5-aminocarbonylphenyl;

k. R² is 2-chloro-5-aminosulfonylphenyl;

l. R² is 2-fluoro-6-trifluoromethylphenyl;

m. R² is 2-chloro-5-methylsulfonylphenyl;

n. R² is 2-chloro-5-dimethylaminosulfonylphenyl;

o. R² is 2-trifluoromethyl-4-chlorophenyl; or the pharmaceuticallyacceptable salts of said compounds.

A group of compounds which is preferred among the R Group of compoundsdesignated the W Group, contains those compounds wherein

R² is a five to six membered nonaromatic heterocyclic ring having one totwo heteroatoms selected independently from nitrogen, sulfur and oxygenor R² is unsubstituted (C₁-C₄)alkyl, unsubstituted (C₃-C₇)cycloalkyl orphenyl(C₁-C₄)alkyl, wherein said phenyl(C₁-C₄)alkyl is optionally mono-or di-substituted independently with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamirto substituents are optionally mono-substitutedwith hydroxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tofive fluorines;

or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the R Group of compoundsdesignated the X Group, contains those compounds wherein

R² is a bicyclic ring consisting of two fused five and/or six memberedpartially saturated, fully saturated or fully unsaturated rings takenindependently having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen, said R² substituent optionally substitutedon carbon or nitrogen with up to three substituents independentlyselected from R⁶, R⁷ and R⁸, wherein one of R⁶, R⁷ and R⁸ is optionallya partially saturated, fully saturated, or fully unsaturated three toseven membered ring optionally having one to three heteroatoms selectedindependently from oxygen, sulfur and nitrogen optionally substitutedwith (C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸ are optionally hydroxy,nitro, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino or(C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tonine fluorines,

or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the X Group of compoundsdesignated the Y Group, contains those compounds wherein

R¹ is (C₃-C₇)cycloalkyl; and

R² is a bicyclic ring consisting of two fused five and/or six memberedpartially saturated, fully saturated or fully unsaturated rings takenindependently having one to three heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen,

said R² bicyclic ring is optionally mono-substituted on carbon ornitrogen with a fully saturated or fully unsaturated five to sixmembered ring optionally having one to two heteroatoms selectedindependently from oxygen, sulfur and nitrogen, said ring optionallymono-substituted with (C₁-C₄)alkyl

said R² bicyclic ring is also optionally mono- or di-substitutedindependently on carbon or nitrogen with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C4)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino are optionallymono-substituted with hydroxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoylamino, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkylaminosulfonyl oroptionally substituted with one to nine fluorines or thepharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the Y Group of compoundsdesignated the Z Group, contains those compounds wherein

R¹ is cyclopropyl; and

R² is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl,cinnolinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl,benzodioxolyl, benzirmidazolyl, indazolyl, indolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzoxadiazolyl or benzothiadiazolyl ring,

wherein said R² bicyclic ring is optionally mono- or di-substitutedindependently on carbon or nitrogen with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino substituents are optionally mono-substitutedwith hydroxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tofive fluorines;

or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the Z Group of compoundsdesignated the AA Group, contains those compounds wherein

R² is a quinolinyl, isoquinolinyl, indazolyl or benzimidazolyl ring,

wherein said R² bicyclic ring is optionally mono- or di-substitutedindependently with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl,

wherein said (C₁-C₄)alkoxy or (C₁-C₄)alkyl substituents are optionallymono-substituted with hydroxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto five fluorines; or the pharmaceutically acceptable salts thereof.

Especially preferred compounds of Formula I are the compounds

[5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidine; or

[5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine;

or the pharmaceutically acceptable salts of said compounds.

Preferred salts of the immediately preceding compound are the mono -ordi-mesylate salts.

Other especially preferred compounds of Formula I are the compounds

[1-(8-Bromoquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(6-Chloroquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(Indazol-7-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(Benzimidazol-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(1-Isoquinolyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;

[5-Cyclopropyl-1-(4-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;

or the pharmaceutically acceptable salts of said compounds.

Especially preferred compounds within the AA Group are compounds wherein

a. R² is 8-bromoquinolin-5-yl;

b. R² is 6-chloroquinolin-5-yl;

c. R² is indazol-7-yl;

d. R² is benzimidazol-5-yl;

e. R² is 1-isoquinolyl;

f. R² is 4-quinolinyl;

or the pharmaceutically acceptable salts of said compounds.

A preferred group of compounds, designated the BB Group, contains thosecomounds having the Formula I as shown above wherein Z is

R¹ is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl,said (C_(1-C) ₄)alkyl optionally substituted with from one to ninefluorines, said R¹ substituent optionally mono- or di-substitutedindependently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinylor (C₁-C₄)alkylsulfonyl; and

R² is a five to six membered nonaromatic heterocyclic ring having one totwo heteroatoms selected independently from nitrogen, sulfur and oxygenor R² is unsubstituted (C₁-C₄)alkyl or unsubstituted (C₃-C₇)cycloalkyl;or R² is phenyl(C₁-C₄)alkyl, or a bicyclic ring consisting of two fusedfive and/or six membered partially saturated, fully saturated or fullyunsaturated rings taken independently having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen, said R²substituents optionally substituted on carbon or nitrogen with up tothree substituents independently selected from R⁶, R⁷ and R⁸, whereinone of R⁶, R⁷ and R⁸ is optionally a partially saturated, fullysaturated, or fully unsaturated three to seven membered ring optionallyhaving one to three heteroatoms selected independently from oxygen,sulfur and nitrogen optionally substituted with (C₁-C₄)alkyl andadditionally R⁶, R⁷ and R⁸ are optionally hydroxy, nitro, halo,(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino or(C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines,

or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the BB Group of compoundsdesignated the CC Group, contains those compounds wherein

R¹ is (C₁-C₄)alkyl; and

R² is a bicyclic ring consisting of two fused five and/or six memberedpartially saturated, fully saturated or fully unsaturated rings takenindependently having one to three heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen,

said R² bicyclic ring is optionally mono-substituted on carbon ornitrogen with a fully saturated or fully unsaturated five to sixmembered ring optionally having one to two heteroatoms selectedindependently from oxygen, sulfur and nitrogen, said ring optionallymono-substituted with (C₁-C₄)alkyl

said R² bicyclic ring is also optionally mono- or di-substitutedindependently on carbon or nitrogen with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino are optionallymono-substituted with hydroxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoylamino, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkylaminosulfonyl oroptionally substituted with one to nine fluorines or thepharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the CC Group of compoundsdesignated the DD Group, contains those compounds wherein

R² is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl,cinnolinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl,benzodioxolyl, benzirnidazolyl, indazolyl, indolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzoxadiazolyl or benzothiadiazolyl ring,

wherein said R² bicyclic ring is optionally mono- or di-substitutedindependently with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino substituents are optionally mono-substitutedwith hydroxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tofive fluorines;

or the pharmaceutically acceptable salts thereof.

Especially preferred compounds of Formula I are the compounds

[1-(Indazol-6-yl)-5-ethyl-1H-pyrazole-4carbonyl]guanidine;

[1-(Indazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(Benzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(1-Methylbenzimidazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine

[1-(5-Quinolinyl)-5-n-propyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(5-Quinolinyl)-5-isopropyl-1H-pyrazole-4-carbonyl]guanidine;

[5-Ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;

[1-(2-Methylbenzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(1,4-Benzodioxan-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(Benzotriazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(3-Chloroindazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(5-Quinolinyl)-5-butyl-1H-pyrazole-4-carbonyl]guanidine;

[5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;

[5-lsopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;

or pharmaceutically acceptable salts of said compounds.

Especially preferred compounds within the DD Group are compounds wherein

a.

R¹ is ethyl; and

R² is indazol-6-yl;

b.

R¹ is ethyl; and

R² is indazol-5-yl;

c.

R¹ is ethyl; and

R² is benzimidazol-5-yl;

d.

R¹ is ethyl; and

R² is 1-methylbenzimidazol-6-yl;

e.

R¹ is n-propyl; and

R² is 5-quinolinyl;

f.

R¹ is isopropyl; and

R² is 5-quinolinyl;

g.

R¹ is ethyl; and

R² is 6-quinolinyl;

h.

R¹ is ethyl; and

R² is 2-methylbenzimidazol-5-yl;

i.

R¹ is ethyl; and

R² is 1,4-benzodioxan-6-yl;

j.

R¹ is ethyl; and

R² is benzotriazol-5-yl;

k.

R¹ is ethyl; and

R² is 3-Chloroindazol-5-yl;

l.

R¹ is butyl; and

R² is 5-quinolinyl;

m.

R¹ is n-propyl; and

R² is 6-quinolinyl;

n.

R¹ is isopropyl; and

R² is 6-quinolinyl;

or the pharmaceutically acceptable salts of said compounds.

A preferred group of compounds, designated the EE Group, contains thosecompounds having the Formula I as shown above wherein Z is

R¹ is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl,said (C₁-C₄)alkyl optionally substituted with from one to ninefluorines, said R¹ substituent optionally mono- or di-substitutedindependently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinylor (C₁-C₄)alkylsulfonyl; and

R² is a five to six membered nonaromatic heterocyclic ring having one totwo heteroatoms selected independently from nitrogen, sulfur and oxygenor R² is unsubstituted (C₁-C₄)alkyl or unsubstituted (C₃-C₇)cycloalkyl;or R² is phenyl(C₁-C₄)alkyl, or a bicyclic ring consisting of two fusedfive and/or six membered partially saturated, fully saturated or fullyunsaturated rings taken independently having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen, said R²substituents optionally substituted on carbon or nitrogen with up tothree substituents independently selected from R⁶, R⁷ and R⁸, whereinone of R⁶, R⁷ and R⁸ is optionally a partially saturated, fullysaturated, or fully unsaturated three to seven membered ring optionallyhaving one to three heteroatoms selected independently from oxygen,sulfur and nitrogen optionally substituted with (C₁-C₄)alkyl andadditionally R⁶, R⁷ and, R⁸ are optionally hydroxy, nitro, halo,(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino or(C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines,

or the, pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the EE Group of compoundsdesignated the FF Group, contains those compounds wherein

R¹ is (C₁-C₄)alkyl; and

R² is a bicyclic ring consisting of two fused five and/or six memberedpartially saturated, fully saturated or fully unsaturated rings takenindependently having one to three heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen,

said R² bicyclic ring is optionally mono-substituted on carbon ornitrogen with a fully saturated or fully unsaturated five to sixmembered ring optionally having one to two heteroatoms selectedindependently from oxygen, sulfur and nitrogen, said ring optionallymono-substituted with (C₁-C₄)alkyl

said R² bicyclic ring is also optionally mono- or di-substitutedindependently on carbon or nitrogen with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino are optionallymono-substituted with hydroxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoylamino, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkylaminosulfonyl oroptionally substituted with one to nine fluorines.

or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the FF Group of compoundsdesignated the GG Group, contains those compounds wherein

R² is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl,cinnolinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl,benzodioxolyl, benzimidazolyl, indazolyl, indolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzoxadiazolyl or benzothiadiazolyl ring,

wherein said R² bicyclic ring is optionally mono- or di-substitutedindependently with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkylaminosulfonyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino substituents are optionally mono-substitutedwith hydroxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tofive fluorines;

or the pharmaceutically acceptable salts thereof.

Especially preferred compounds of Formula I are the compounds

[1-(Indazol-7-yl)-3-methyl-1H-pyrazole-4-carbonyl]guanidine;

[1-(2,1,3-Benzothiadiazol-4-yl)-3-methyl-1H-pyrazole-4-carbonyl]guanidine;

[3-Methyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine;

or the pharmaceutically acceptable salts of said compounds.

Especially preferred compounds within the GG Group of compounds arecompounds wherein

a.

R¹ is methyl; and

R² is indazol-7-yl;

b.

R¹ is methyl; and

R² is 2,1,3-benzothiadiazol-4-yl;

c.

R¹ is methyl; and

R² is quinolin-5-yl;

or the pharmaceutically acceptable salts of said compounds.

A preferred group of compounds, designated the HH Group, contains thosecompounds having the Formula I as shown above wherein Z is

R⁴ is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl,said (C₁-C₄)alkyl optionally substituted with from one to ninefluorines, said R⁴ substituent optionally mono- or di-substitutedindependently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinylor (C₁-C₄)alkylsulfonyl; and

R⁵ is a five to six membered nonaromatic heterocyclic ring having one totwo heteroatoms selected independently from nitrogen, sulfur and oxygenor R⁵ is unsubstituted (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl; or R⁵ isphenyl(C₁-C₄)alkyl, or a bicyclic ring consisting of two fused fiveand/or six membered partially saturated, fully saturated or fullyunsaturated rings taken independently having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen, said R⁵substituents optionally substituted on carbon or nitrogen with; up tothree substituents independently selected from R⁶, R⁷ and R⁸, whereinone of R⁶, R⁷ and R⁸ is optionally a partially saturated, fullysaturated, or fully unsaturated three to seven membered ring optionallyhaving one to three heteroatoms selected independently from oxygen,sulfur and nitrogen optionally substituted with (C₁-C₄)alkyl andadditionally R⁶, R⁷ and R⁸ are optionally hydroxy, nitro, halo,(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino or(C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines,

or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the HH Group of compoundsdesignated the II Group, contains those compounds wherein

R⁴ is (C₁-C₄)alkyl; and

R⁵ is a bicyclic ring consisting of two fused five and/or six memberedpartially saturated, fully saturated or fully unsaturated rings takenindependently having one to three heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen,

said R⁵ bicyclic ring is optionally mono-substituted on carbon with afully saturated or fully unsaturated five to six membered ringoptionally having one to two heteroatoms selected independently fromoxygen, sulfur and nitrogen, said ring optionally mono-substituted with(C₁-C₄)alkyl

said R⁵ bicyclic ring is also optionally mono- or di-substitutedindependently on carbon or nitrogen with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkysulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkythio, mono-N— or di-N,N—(C₁-C₄)alkylamino are optionallymono-substituted with hydroxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoylamino, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,(C₀-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkylaminosulfonyl oroptionally substituted with one to nine fluorines.

or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the II Group of compoundsdesignated the JJ Group, contains those compounds wherein

R⁵ is a quinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl,cinnolinyl, benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl,benzodioxolyl, benzitnidazolyl, indazolyl, indolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzoxadiazolyl or benzothiadiazolyl ring,

wherein said R⁵ bicyclic ring is optionally mono- or di-substitutedindependently with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino substituents are optionally mono-substitutedwith hydroxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tofive fluorines;

or the pharmaceutically acceptable salts thereof.

A preferred group of compounds, designated the KK Group, contains thosecompounds having the Formula I as shown above wherein Z is

Z is

R² is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, M or M(C₁-C₄)alkyl, any of saidprevious (C₁-C₄)alkyl moieties optionally having from one to ninefluorines; said (C₁-C₄)alkyl or (C₃-C₄)cycloalkyl optionally mono- ordi-substituted independently with hydroxy; (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,(C₁-C₄)alkyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl; and said (C₃-C₄)cycloalkyl optionallyhaving from one to seven fluorines;

wherein M is a partially saturated, fully saturated or fully unsaturatedfive to eight membered ring optionally having one to three heteroatomsselected independently from oxygen, sulfur and nitrogen, or, a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated three to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

said M is optionally substituted, on one ring if the moiety ismonocyclic, or one or both rings if the moiety is bicyclic, on carbon ornitrogen with up to three substituents independently selected from R⁶,R⁷ and R⁸, wherein one of R⁶, R⁷ and R⁸ is optionally a partiallysaturated, fully saturated, or fully unsaturated three to seven memberedring optionally having one to three heteroatoms selected independentlyfrom oxygen, sulfur and nitrogen optionally substituted with(C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸ are optionally hydroxy,nitro, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino or(C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines; and

R³ is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl,said (C₁-C₄)alkyl optionally substituted with from one to ninefluorines, said R³ substituent optionally mono- or di-substitutedindependently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or (C₁-C₄)alkyl, or apharmaceutically acceptable salt thereof.

A group of compounds which is preferred among the KK Group of compoundsdesignated the LL Group, contains those compounds wherein

R³ is (C₁-C₄)alkyl;

R² is phenyl, said phenyl optionally mono-substituted on carbon with afully saturated or fully unsaturated five to six membered ringoptionally having one to two heteroatoms selected independently fromoxygen, sulfur and nitrogen, said ring optionally mono-substituted with(C₁-C₄)alkyl said R² ring is also optionally mono- or di-substitutedindependently on carbon with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino are optionallymono-substituted with hydroxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoylamino, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkylaminosulfonyl oroptionally substituted with one to nine fluorines,

or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the KK Group of compoundsdesignated the MM Group, contains those compounds wherein

R³ is (C₁-C₄)alkyl;

R² is a bicyclic ring consisting of two fused five and/or six memberedpartially saturated, fully saturated or fully unsaturated rings takenindependently

said R² bicyclic ring is optionally mono-substituted on carbon with afully saturated or fully unsaturated five to six membered ringoptionally having one to two heteroatoms selected independently fromoxygen, sulfur and nitrogen, said ring optionally mono-substituted with(C₁-C₄)alkyl

said R² bicyclic ring is also optionally mono- or di-substitutedindependently on carbon with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylamirtosulfonyl

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino are optionallymono-substituted with hydroxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoylamino, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkylaminosulfonyl oroptionally substituted with one to nine fluorines,

or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the KK Group of compoundsdesignated the NN Group, contains those compounds wherein

R³ is (C₁-C₄)alkyl;

R² is a five to six membered monocyclic aromatic ring having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

said R² ring is optionally mono-substituted on carbon with a fullysaturated or fully unsaturated five to six membered ring optionallyhaving one to two heteroatoms selected independently from oxygen, sulfurand nitrogen, said ring optionally mono-substituted with (C₁-C₄)alkyl

said R² ring is also optionally mono- or di-substituted independently oncarbon or nitrogen with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino are optionallymono-substituted with hydroxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoylamino, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkyliminosulfonyl oroptionally substituted with one to nine fluorines

or the pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the KK Group of compoundsdesignated the OO Group, contains those compounds wherein

R³ is (C₁-C₄)alkyl;

R² is a bicyclic ring consisting of two fused five and/or six memberedpartially saturated, fully saturated or fully unsaturated rings takenindependently having one to three heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen,

said R² bicyclic ring is optionally mono-substituted on carbon ornitrogen with a fully saturated or fully unsaturated five to sixmembered ring optionally having one to two heteroatoms selectedindependently from oxygen, sulfur and nitrogen, said ring optionallymono-substituted with (C₁-C₄)alkyl

said R² bicyclic ring is also optionally mono- or di-substitutedindependently on carbon or nitrogen with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C₇)alkanoyl,(C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylamino are optionallymono-substituted with hydroxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoylamino, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkylaminosulfonyl oroptionally substituted with one to nine fluorines

or the pharmaceutically acceptable salts thereof.

Another aspect of this invention is directed to the esters of

5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate,

5-methyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylate,

5-methyl-1-naphthalenyl-1H-pyrazole-4-carboxylate,

5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carboxylate,

5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate,

5-ethyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate or

n-butyl 1-(isoquinolin-5-yl)-3-methyl-1H-pyrazole-4-carboxylate whereinsaid esters are benzyl, (C₁-C₆)alkyl or (C₄-C₈)cycloalkyl, said(C₄-C₈)cycloalkyl optionally mono-substituted with (C₁-C₄)alkyl

or a salt of said esters.

Yet another aspect of this invention is directed to the followingcompounds

5-methyl-2-(5-quinolinyl)-2H-1,2,3-triazole-4-carboxylic acid,

5-methyl-2-(5-isoquinolinyl)-2H-1,2,3-triazole-4-carboxylic acid,

2-(1-nabphthalenyl)-5-methyl-2H-1,2,3-triazole-4-carboxylic acid,

5-methyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylic acid,

5-methyl-1-naphthalenyl-1H-pyrazole-4-carboxylic acid,

5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carboxylic acid,

5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carboxylic acid,

5-ethyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid,

5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid or

1-(isoquinolin-5-yl)-3-methyl-1H-pyrazole-4-carboxylic acid or the acidchlorides thereof or a salt of said compounds or of said acid chlorides.

Another aspect of this invention is a method of treating a mammal (e.g.,human) having a disease or condition mediated by NHE-1 by administeringa pharmaceutically acceptable amount of a compound of Formula I, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug to the mammal.

Another aspect of this invention is directed to a method of reducingtissue damage (e.g., substantially preventing tissue damage, inducingtissue protection) resulting from ischemia comprising administering to amammal (e.g., a female or male human) in need of such treatment atherapeutically effective amount of a compound of Formula I a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug.

Preferred ischemic tissues taken individually or as a group are whereinthe ischemic tissue is cardiac, brain, liver, kidney, lung, gut,skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue,the vasculature, or intestinal tissue.

An especially preferred ischemic tissue is cardiac tissue.

It is especially preferred that the compounds are administered toprevent perioperative myocardial ischemic injury.

Preferably, the compounds of this invention are administeredprophylactically.

The ischemic damage may occur during organ transplantation.

Preferably, the compounds of this invention are administered prior to,during or shortly after, cardiac surgery or non-Cardiac surgery.

In one aspect of this invention a compound of Formula I is administeredlocally.

A preferred dosage is about 0.001 to 100 mg/kg/day of the Formula Icompound a prodrug thereof. An especially preferred dosage is about 0.01to 50 mg/kg/day of a compound of Formula I, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug.

Another aspect of this invention is directed to a method of reducingmyocardial tissue damage (e.g., substantially preventing tissue damage,inducing tissue protection) during surgery (e.g., coronary artery bypassgrafting (CABG) surgeries, vascular surgeries, percutaneous transluminalcoronary angioplasty (PTCA) or any percutaneous transluminal coronaryintervention (PTC1), organ transplantation, or other non-Cardiacsurgeries) comprising administering to a mammal (e.g., a female or malehuman) a therapeutically effective amount of a compound of Formula I, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug.

Another aspect of this invention is directed to a method of reducingmyocardial tissue damage (e.g., substantially preventing tissue damage,inducing tissue protection) in patients presenting with ongoing cardiac(acute coronary syndromes, e.g. myocardial infarction or unstableangina) or cerebral ischemic events (e.g. stroke) comprisingadministering to a mammal (e.g., a female or male human) atherapeutically effective amount of a compound of Formula I, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug.

Another aspect of this invention is directed to a chronic method ofreducing myocardial tissue damage (e.g., substantially preventing tissuedamage, inducing tissue protection) in a patient with diagnosed coronaryheart disease (e.g. previous myocardial infarction or unstable angina)or patients who are at high risk for myocardial infarction (age >65 andtwo or more risk factors for coronary heart disease) comprisingadministering to a mammal (e.g., a female or male human) atherapeutically effective amount of a compound of Formula I, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug.

Another aspect of this invention is directed to a method of preventingischemic damage comprising the chronic oral administration to a mammalin need of such treatment of a therapeutically effective amount of acompound of Formula I a prodrug of said compound or a pharmaceuticallyacceptable salt of said compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingcardiovascular diseases comprising administering to a mammal (e.g., afemale or male human) a therapeutically effective amount of a compoundof Formula I, a prodrug thereof, or a pharmaceutically acceptable saltof said compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingarteriosclerosis comprising administering to a mammal (e.g., a female ormale human) a therapeutically effective amount of a compound of FormulaI, a prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug.

Another aspect of this invention is directed to a method for treatinghypertension comprising administering to a mammal (e.g., a female ormale human) a therapeutically effective amount of a compound of FormulaI, a prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug.

Another aspect of this invention is directed to a method for treatingarrhythmia comprising administering to a mammal (e.g., a female or malehuman) a therapeutically effective amount of a compound of Formula I, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug.

Another aspect of this invention is directed to a method for treatingangina pectoris comprising administering to a mammal (e.g., a female ormale human) a therapeutically effective amount of a compound of FormulaI, a prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug.

Another aspect of this invention is directed to a method for treatingcardiac hypertrophy comprising administering to a mammal (e.g., a femaleor male human) a therapeutically effective amount of a compound ofFormula I, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingrenal diseases comprising administering to a mammal (e.g., a female ormale human) a therapeutically effective amount of a compound of FormulaI, a prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug.

Another aspect of this invention is directed to a method for treatingdiabetic complications comprising administering to a mammal (e.g., afemale or male human) a therapeutically effective amount of a compoundof Formula I, a prodrug thereof, or a pharmaceutically acceptable saltof said compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingrestenosis comprising administering to a mammal (e.g., a female or malehuman) a therapeutically effective amount of a compound of Formula I, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug.

Another aspect of this invention is directed to a method for treatingdiseases of cell proliferation comprising administering to a mammal(e.g., a female or male human) a therapeutically effective amount of acompound of Formula I, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingcancerous diseases comprising administering to a mammal (e.g., a femaleor male human) a therapeutically effective amount of a compound ofFormula I, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingfibrotic diseases comprising administering to a mammal (e.g., a femaleor male human) a therapeutically effective amount of a compound ofFormula I, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingglomerular nephrosclerosis comprising administering to a mammal (e.g., afemale or male human) a therapeutically effective amount of a compoundof Formula I, a prodrug thereof, or a pharmaceutically acceptable saltof said compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingorgan hypertrophies or hyperplasias comprising administering to a mammal(e.g., a female or male human) a therapeutically effective amount of acompound of Formula I, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingpulmonary fibrosis comprising administering to a mammal (e.g., a femaleor male human) a therapeutically effective amount of a compound ofFormula I, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingcerebro ischemic disorders comprising administering to a mammal (e.g., afemale or male human) a therapeutically effective amount of a compoundof Formula I, a prodrug thereof, or a pharmaceutically acceptable saltof said compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingmyocardial stunning comprising administering to a mammal (e.g., a femaleor male human) a therapeutically effective amount of a compound ofFormula I, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingmyocardial dysfunction comprising administering to a mammal (e.g., afemale or male human) a therapeutically effective amount of a compoundof Formula I, a prodrug thereof, or a pharmaceutically acceptable saltof said compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingcerebrovascular diseases comprising administering to a mammal (e.g., afemale or male human) a therapeutically effective amount of a compoundof Formula I, a prodrug thereof, or a pharmaceutically acceptable saltof said compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingorgan hypertrophies or hyperplasias comprising administering to a mammal(e.g., a female or male human) a therapeutically effective amount of acompound of Formula I, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug.

Another aspect of this invention is directed to a method for treatingorgan hypertrophies or hyperplasias comprising administering to a mammal(e.g., a female or male human) a therapeutically effective amount of acompound of Formula I, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug.

This invention is also directed to pharmaceutical compositions whichcomprise a therapeutically effective amount of a compound of Formula I,a prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thereduction of tissue damage resulting from ischemia which comprise atherapeutically effective amount of a compound of Formula I, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug and a pharmaceutically acceptable carrier.

Yet another aspect of this invention are combinations of a compound ofFormula I, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug and other compounds as described below.

Yet another aspect of this invention is directed to pharmaceuticalcompositions comprising a compound of Formula I or a pharmaceuticallyacceptable salt or prodrug thereof and a cardiovascular agent and forthe use of such compositions for the reduction of tissue damageresulting from tissue ischemia in mammals (e.g., humans, male orfemale).

In the above pharmaceutical compositions and methods preferred Formula Icompounds include the preferred groups of compounds described abovelabeled as Group A-to Group OO.

Another aspect of this invention is a method of reducing tissue damage(e.g., substantially preventing tissue damage, inducing tissueprotection) resulting from or which could result from ischemiacomprising administering to a mammal (e.g., a female or male human)

a. a first compound, said first compound being a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug; and

b. a second compound, said second compound being a cardiovascular agent

wherein the amounts of the first and second compounds result in atherapeutic effect.

Another aspect of this invention is a kit comprising:

a. a therapeutically effective amount of a Formula I compound, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug and a pharmaceutically acceptable carrier, vehicle ordiluent in a first unit dosage form;

b. a therapeutically effective amount of a cardiovascular agent and apharmaceutically acceptable carrier, vehicle or diluent in a second unitdosage form; and

c. means for containing said first and second dosage forms wherein theamounts of the first and second compounds result in a therapeuticeffect.

In the above combination compositions, combination methods and kits,preferably the cardiovascular agents are for example, β-blockers (e.g.,acebutolol, atenolol, bopindolol, labetolol, mepindolol, nadolol,oxprenol, pindolol, propranolol, sotalol), calcium channel blockers(e.g., amlodipine, nifedipine, nisoldipine, nitrendipine, verapamil),potassium channel openers, adenosine, adenosine agonists, ACE inhibitors(e.g., captopril, enalapril), nitrates (e.g., isosorbide dinitrate,isosorbide 5-mononitrate, glyceryl trinitrate), diuretics (e.g.,hydrochlorothiazide, indapamide, piretanide, xipamide), glycosides(e.g., digoxin, metildigoxin), thrombolytics (e.g. tPA), plateletinhibitors (e.g., reopro), aspirin, dipyridamol, potassium chloride,clonidine, prazosin or adenosine A₃ receptor agonists.

In the above combination compositions, combination methods and kitspreferred Formula I compounds include the preferred groups of compoundsdescribed above labeled as Group A to Group OO.

This invention is also directed to a pharmaceutical combinationcomposition comprising: a therapeutically effective amount of acomposition comprising

a first compound, said first compound being a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug;

a second compound, said second compound being a glycogen phosphorylaseinhibitor; and/or optionally

a pharmaceutical carrier, vehicle or diluent.

Another aspect of this invention is a method of reducing tissue damage(e.g., substantially preventing tissue damage, inducing tissueprotection) resulting from or which could result from ischemiacomprising administering to a mammal (e.g., a female or male human)

a. a first compound, said first compound being a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug; and

b. a second compound, said second compound being a glycogenphosphorylase inhibitor wherein the amounts of the first and secondcompounds result in a therapeutic effect.

Another aspect of this invention is a kit comprising:

a. a therapeutically effective amount of a Formula I compound, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug and a pharmaceutically acceptable carrier, vehicle ordiluent in a first unit dosage form;

b. a therapeutically effective amount of a glycogen phosphorylaseinhibitor and a pharmaceutically acceptable carrier, vehicle or diluentin a second unit dosage form; and

c. means for containing said first and second dosage forms wherein theamounts of the first and second compounds result in a therapeuticeffect.

In the above combination compositions, combination methods and kitspreferred Formula I compounds include the preferred groups of compoundsdescribed above labeled as Group A to Group OO.

In the above combination compositions, combination methods and kitspreferred glycogen phosphorylase inhibitors are

5-chloro-1H-indole-2-carboxylic acid[(1S)-((R)-hydroxy-dimethylcarbamoyl-methyl)-2-phenyl-ethyl]-amide,

5,6-dichloro-1H-indole-2-carboxylic acid{(1S)-[(R)-hydroxy-(methoxy-methyl-carbamoyl)-methyl]-2-phenyl-ethyl}-amide,

5-chloro-1H-indole-2-carboxylic acid{(1S)-[(R)-hydroxy-(methoxy-methyl-carbamoyl)-methyl]-2-phenyl-ethyl}-amide,

5-chloro-1H-indole-2-carboxylic acid((1S)-{(R)-hydroxy-[(2-hydroxy-ethyl)-methyl-carbamoyl]-methyl}-2-phenyl-ethyl)-amide,

5-chloro-1H-indole-2-carboxylic acid{(1S)-[(R)-hydroxy-(methyl-pyridin-2-yl-carbamoyl)-methyl]-2-phenyl-ethyl}-amideor

5-chloro-1H-indole-2-carboxylic acid((1S)-{(R)-hydroxy-[methyl-(2-pyridin-2-yl-ethyl)-carbamoyl]-methyl}-2-phenyl-ethyl)-amide.

5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-amidehydrochloride,

5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-(3-hydroxy-azetidin-1-yl)-3-oxo-propyl]-amide,

5-chloro-1H-indole-2-carboxylic acid((1S)-benzyl-(2R)-hydroxy-3-isoxazolidin-2-yl-3-oxo-propyl)-amide,

5-Chloro-1H-indole-2-carboxylic acid((1S)-benzyl-(2R)-hydroxy-3-[1,2]oxazinan-2-yl-3-oxo-propyl)-amide,

5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3S)-hydroxy-pyrrolidin-1-yl)-3-oxo-propyl]-amide,

5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide,

5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amideor

5-chloro-1H-indole-2-carboxylic acid((1S)-benzyl-(2R)-hydroxy-3-morpholin-4-yl-3-oxo-propyl)-amide.

5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxyimino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid[2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid[2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid[2-(1,1-dioxo-thiazolidin-3-yl)-2-oxo-ethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid(2-oxo-2-thiazolidin-3-yl-ethyl)-amide,

5-chloro-1H-indole-2-carboxylic acid[(1S)-(4-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-((3RS)-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid[2-oxo-2-((1RS)-oxo-1-thiazolidin-3-yl)-ethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid[(1S)-(2-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,

5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide,

5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxyimino-azetidin-1-yl)-2-oxo-ethyl]-amide or

5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(4-hydroxyimino-piperidin-1-yl)-2-oxo-ethyl]-amide.

This invention is also directed to a pharmaceutical combinationcomposition comprising: a therapeutically effective amount of acomposition comprising

a first compound, said first compound being a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug;

a second compound, said second compound being an aldose reductaseinhibitor; and/or optionally

a pharmaceutical carrier, vehicle or diluent.

Another aspect of this invention is a method of reducing tissue damage(e.g., substantially preventing tissue damage, inducing tissueprotection) resulting from or which could result from ischemiacomprising administering to a mammal (e.g., a female or male human)

a. a first compound, said first compound being a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug; and

b. a second compound, said second compound being an aldose reductaseinhibitor

wherein the amounts of the first and second compounds result in atherapeutic effect.

Another aspect of this invention is a kit comprising:

a. a therapeutically effective amount of a Formula I compound, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug and a pharmaceutically acceptable carrier, vehicle ordiluent in a first unit dosage form;

b. a therapeutically effective amount of an aldose reductase inhibitorand a pharmaceutically acceptable carrier, vehicle or diluent in asecond unit dosage form; and

c. means for containing said first and second dosage forms wherein theamounts of the first and second compounds result in a therapeuticeffect.

In the above combination compositions, combination methods and kitspreferred Formula I compounds include the preferred groups of compoundsdescribed above labeled as Group A to Group OO.

In the above combination compositions, combination methods and kits apreferred aldose reductase inhibitor is zopolrestat: 1-phthalazineaceticacid,3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]-.

In the methods of treatment as applied to the combinations describedabove the following are preferred administration routes, modes etc.

Preferred ischemic tissues taken individually or as a group are whereinthe ischemic tissue is cardiac, brain, liver, kidney, lung, gut,skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue,the vasculature, or intestinal tissue.

An especially preferred ischemic tissue is cardiac tissue.

It is especially preferred that the compounds are administered toprevent perioperative myocardial ischemic injury.

Preferably, the compounds of this invention are administeredprophylactically.

The ischemic damage may occur during organ transplantation.

Preferably, the compounds of this invention are administered prior to,during or shortly after, cardiac surgery or non-cardiac surgery.

In one aspect of this invention the compounds are administered locally.

In one aspect of this method myocardial tissue damage is reduced duringsurgery.

In another aspect of this method myocardial tissue damage is reduced inpatients presenting with ongoing cardiac or cerebral ischemic events.

In yet another aspect of this method myocardial tissue damage is reducedby chronic administration of the combination in a patient with diagnosedcoronary heart disease.

The term “reduction” is intended to include partial prevention orprevention which, although greater than that which would result fromtaking no compound or from taking a placebo, is less than 100% inaddition to substantially total prevention.

The term “damage resulting from ischemia” as employed herein refers toconditions directly associated with reduced blood flow to tissue, forexample due to a clot or obstruction of blood vessels which supply bloodto the subject tissue and which result, inter alia, in lowered oxygentransport to such tissue, impaired tissue performance, tissuedysfunction and/or necrosis. Alternatively, where blood flow or organperfusion may be quantitatively adequate, the oxygen carrying capacityof the blood or organ perfusion medium may be reduced, e.g., in hypoxicenvironment, such that oxygen supply to the tissue is lowered, andimpaired tissue performance, tissue dysfunction, and/or tissue necrosisensues.

The term “treating”, “treat” or “treatment” as used herein includespreventative (e.g., prophylactic) and palliative treatment.

By “pharmaceutically acceptable” it is meant the carrier, diluent,excipients, and/or salt must be compatible with the other ingredients ofthe formulation, and not deleterious to the recipient thereof.

The expression “prodrug” refers to compounds that are drug precursorswhich following administration, release the drug in vivo via somechemical or physiological process (e.g., a prodrug on being brought tothe physiological pH or through enzyme action is converted to thedesired drug form).

Exemplary five to six membered aromatic rings optionally having one ortwo heteroatoms selected independently from oxygen, nitrogen and sulfurare phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl,pyrimidinyl and pyrazinyl.

Exemplary partially saturated, fully saturated or fully unsaturated fiveto eight membered rings optionally having one to three heteroatomsselected independently from oxygen, sulfur and nitrogen are cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further exemplary fivemembered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl,2H-imidazolyl 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl,3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-trizaolyl,1,3,4-thiadiazolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl,1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl and1,3-oxathiolyl.

Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl,pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomoirpholinyl, pyridazinyl, pyrimidinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl,6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl,4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl,p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl and1,4,2-oxadiazinyl.

Further exemplary seven membered rings are azepinyl, oxepinyl, thiepinyland 1,2,4-diazepinyl.

Further exemplary eight membered rings are cyclooctyl, cyclooctenyl andcyclooctadienyl.

Exemplary bicyclic rings consisting of two fused partially saturated,fully saturated or fully unsaturated five and/or six membered rings,taken independently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen are indolizinyl, indolyl,isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl,benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl,1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl,benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl,2H-1-benzopyranyl, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl,pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl,1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and4H-1,4-benzoxazinyl.

By alkylene is meant saturated hydrocarbon (straight chain or branched)wherein a hydrogen atom is removed from each of the terminal carbons.Exemplary of such groups (assuming the designated length encompases theparticular example) are methylene, ethylene, propylene, butylene,pentylene, hexylene, heptylene).

By halo is meant chloro, bromo, iodo, or fluoro.

By alkyl is meant straight chain saturated hydrocarbon or branchedsaturated hydrocarbon. Exemplary of such alkyl groups (assuming thedesignated length encompasses the particular example) are methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl,neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,hexyl, isohexyl, heptyl and octyl.

By alkoxy is meant straight chain saturated alkyl or branched saturatedalkyl bonded through an oxygen. Exemplary of such alkoxy groups(assuming the designated length encompasses the particular example) aremethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiarybutoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy,isohexoxy, heptoxy and octoxy .

As used herein the term mono-N— or di-N,N—(C₁-C_(x))alkyl . . . refersto the (C₁-C_(x))alkyl moiety taken independently when it isdi-N,N—(C₁-C_(x))alkyl . . . (x refers to integers).

It is to be understood that if a carbocyclic or heterocyclic moiety maybe bonded or otherwise attached to a designated substrate throughdiffering ring atoms without denoting a specific point of attachment,then all possible points are intended, whether through a carbon atom or,for example, a trivalent nitrogen atom. For example, the term “pyridyl”means 2-, 3-, or 4-pyridyl, the term “thienyl” means 2-, or 3-thienyl,and so forth.

The expression “pharmaceutically-acceptable salt” refers to nontoxicanionic salts containing anions such as (but not limited to) chloride,bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate,fumarate, oxalate, lactate, tartrate, citrate, gluconate,methanesulfonate and 4-toluene-sulfonate. Where more than one basicmoiety exists the expression includes multiple salts (e.g., di-salt).The expression also refers to nontoxic cationic salts such as (but notlimited to) sodium, potassium, calcium, magnesium, ammonium orprotonated benzathine (N,N′-dibenzylethylenediamine), choline,ethanolamine, diethanolamine, ethylenediamine, meglamine(N-methyl-glucamine), benethamine (N-benzylphenethylamine), piperazineor tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).

As used herein, the expressions “reaction-inert solvent” and “inertsolvent” refers to a solvent or mixture of solvents which does notinteract with starting materials, reagents, intermediates or products ina manner which adversely affects the yield of the desired product.

The chemist of ordinary skill will recognize that certain compounds ofthis invention will contain one or more atoms which may be in aparticular stereochemical or geometric configuration, giving rise tostereoisomers and configurational isomers. All such isomers and mixturesthereof are included in this invention. Hydrates of the compounds ofthis invention are also included.

DMF means N,N-dimethylformamide. DMSO means dimethyl sulfoxide. THFmeans tetrahydrofuran.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in Formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labelled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of Formula I of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples below, bysubstituting a readily available isotopically labelled reagent for anon-isotopically labelled reagent.

Other features and advantages will be apparent from the specificationand claims which describe the invention.

DETAILED DESCRIPTION OF THE INVENTION

In general the compounds of this invention can be made by processeswhich include processes known in the chemical arts, particularly inlight of the description contained herein. Certain processes for themanufacture of the compounds of this invention are provided as furtherfeatures of the invention and are illustrated by the following reactionschemes. Other processes are described in the experimental section.

Briefly, in general, a compound of the Fomula Z—C(O)OH is coupled withguanidine in the presence of a suitable coupling agent.

According to Scheme I the Formula IA compound, wherein R⁴ is asdescribed above, is dissolved or suspended in an aqueous alkali metalhydroxide solution (e.g. 1 N sodium hydroxide) along with sodium nitriteand the mixture is added to an aqueous acidic solution (e.g. 10% v/vsulfuric acid) at a pH of about 0 at a temperature of about 0° C. toabout 5° C. for about 30 min to about 1 hour. The resulting mixture isfiltered to yield the Formula II oxime. Alternatively, the Formula IAcompound is dissolved in 1:1 acetic acid/propionic acid and solid sodiumnitrite is added at about 0° C. The reaction mixture is stirred at about0° C. for about 2 hours, then poured into ice water and the Formula IIoxime is obtained by filtration.

The Formula II compound is reacted with a Formula III compound, whereinR⁵ is as described above in a protic solvent such as ethanol at atemperature of about 50° C. to about 110° C. for about 10 min to about 1hour to form the Formula IV hydrazone.

The Formula IV hydrazone is cyclized and hydrolyzed to the Formula Vtriazole in an alcoholic solvent such as 2-ethoxyethanol under basicconditions (e.g., potassium hydroxide) at a temperature of about 100° C.to about 175° C. for about ½ hour to about 2 hours followed byacidification to yield the Formula V triazole acid.

The Formula V acid is coupled with guanidine in the presence of asuitable coupling agent. A suitable coupling agent is one whichtransforms a carboxylic acid into a reactive species which forms anamide linkage on reaction with an amine.

The coupling agent may be a reagent which effects this condensation in aone pot process when mixed together with the carboxylic acid andguanidine. Exemplary coupling reagents are1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride-hydroxybenzotriazole (EDC/HBT),dicydohexylcarbodiimide/hydroxybenzotriazole(HBT),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), anddiethylphosphorylcyanide. The coupling is performed in an inert solvent,preferably an aprotic solvent at a temperature of about −20° C. to about50° C. for about 1 to about 48 hours, in the presence of excessguanidine as base. Exemplary solvents include acetonitrile,dichloromethane, dimethylformamide and chloroform or mixtures thereof.

The coupling agent may also be that agent which converts the carboxylicacid to an activated intermediate which is isolated and/or formed in afirst step and allowed to react with guanidine in a second step.Examples of such coupling agents and activated intermediates are thionylchloride or oxalyl chloride to form the acid chloride, cyanuric fluorideto form an acid fluoride or an alkyl chloroformate such as isobutyl orisopropenyl chloroformate or propanephosphonic anhydride(propanephosphonic acid anhydride, PPA) (with a tertiary amine base) toform a mixed anhydride of the carboxylic acid, or carbonyldiimidazole toform an acylimidazole. If the coupling agent is oxalyl chloride, it isadvantageous to employ a small amount of dimethylformamide as cosolventwith another solvent (such as dichloromethane) to catalyze the formationof the acid chloride. This activated acid derivative may be coupled bymixing with excess guanidine in an appropriate solvent together with anappropriate base. Appropriate solvent/base combinations are for example,dichloromethane, dimethylformamide or acetonitrile or mixtures thereofin the presence of excess guanidine as base. Other appropriatesolvent/base combinations include water or a ((C₁-C₅)alcohol) or amixture thereof together with a cosolvent such as dichloromethane,tetrahydrofuran or dioxane and a base such as sodium, potassium orlithium hydroxide in sufficient quantity to consume the acid liberatedin the reaction. Use of these coupling agents and appropriate selectionof solvents and temperatures are known to those skilled in the art orcan be readily determined from the literature. These and other exemplaryconditions useful for coupling carboxylic acids are described inHouben-Weyl, Vol XV, part II, E. Wunsch, Ed., G. Theime Verlag, 1974,Stuttgart; M. Bodansky, Principles of Peptide Synthesis,Springer-Verlag, Berlin 1984; and The Peptides, Analysis, Synthesis andBiology (ed. E. Gross and J. Meienhofer), vols 1-5 (Academic Press, NY1979-1983).

According to Scheme II, the Formula X primary amine wherein R⁵ is asdescribed above is reacted with a Formula XI α-diazo-β-keto-esterwherein R⁴ is as described above, and R is lower alkyl, in the presenceof titanium tetrachloride analogously to the method described in EguchiS. et al. Synthesis 1993, 793 to form the Formula XII triazolecarboxylic acid ester. The Formula XII ester is converted directly tothe acylguanidine XIII by reaction with guanidine in an alcoholicsolvent at a temperature of about 60 to about 110° C., preferablyrefluxing methanol, for a period of 8 to 20 hours.

According to Scheme III, the Formula XV compound wherein R⁴ and R⁵ areas described above is treated with Lawesson's reagent (i.e.,2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) inan aprotic solvent such as dimethoxyethane at a temperature of about 20°C. to about 120° C. for about one to eight hours. The resultingthioamide is treated with an alkylating agent such as methyl iodide in apolar, inert solvent such as acetone, conveniently at ambienttemperature for about eight hours to about forty-eight hours. Theresulting compound is reacted with anhydrous hydrazine in an alcoholicsolvent at a temperature of about 0° C. to about 25° C. for about one toeight hours to provide the Formula XVI compound (analogously asdescribed in Doyle and Kurzer, Synthesis 1974, 583).

The Formula XVI compound is treated with a monoalkyloxalyl chloride inan aprotic solvent at a temperature of about 25° C. to about 50° C. forabout one to eight hours to provide the Formula XVII carboxylic estercompound wherein R is lower alkyl. The Formula XVII ester is directlycoupled with guanidine in an alcoholic solvent at a temperature of about60° C. to about 110° C., preferably refluxing methanol, for a period ofeight to twenty hours, to prepare the Formula XVIII triazole carbonylguanidines.

According to Scheme IV the Formula XX compound wherein R⁵ is asdescribed above is treated with methyl iodide in an inert solvent,conveniently at ambient temperature for about four to twenty-four hours.The resulting compound is reacted with anhydrous R⁴-hydrazine (whereinR⁴ is as described above) in an alcohoic solvent at a temperature ofabout 0° C. to about 25° C. for about one to eight hours to provide theFormula XXI amidrazone compound (analogously as described in Doyle andKurzer, Synthesis 1974, 583).

The Formula XXI compound is treated with a monoalkyloxalyl chloride inan aprotic. solvent at a temperature of about 25° C. to about 50° C. forabout one to eight hours to provide the Formula XXII carboxylic estercompound wherein R is lower alkyl. The Formula XXII ester is directlycoupled with guanidine in an alcoholic solvent at a temperature of about60° C. to about 110° C., preferably refluxing methanol, for a period ofeight to twenty hours to prepare the Formula XXIII triazole carbonylguanidines.

According to Scheme V the Formula XXV compound wherein R¹ is asdescribed above is combined with excess (CH₃O)₂C(R³)N(CH₃)₂(N,N-dimethyl amide dimethyl acetal) wherein R³ is as described above,optionally in the presence of an acid catalyst such as p-toluenesulfonicacid at a temperature of about 90° C. to about 110° C. for about one toabout two hours to prepare the Formula XXVI compound above.

The Formula XXVI compound is cyclized with a Formula XXVII compound,wherein R² is as described above, in an inert solvent such as ethanol ata temperature of about 20° C. to about 30° C. for about 5 minutes toabout one hour followed by heating to a temperature of about 70° C. toabout 110° C. for about two hours to about four hours to form theFormula XXVIII pyrazole.

Alternatively, according to Scheme V the Formula XXV compound, whereinR¹ is as described above, is combined with a triethylorthoester (i.e.,R³C(OEt)₃ wherein R³ is as described above) and acetic anhydride at atemperature of about 120° C. to about 150° C. for about two to aboutfive hours to prepare the Formula XXXI compound.

The Formula XXXI compound is cyclized with a Formula XXVII compound,wherein R² is as described above, to form the Formula XXVIII pyrazole.

The Formula XXVIII pyrazole is hydrolyzed with a base such as sodiumhydroxide or lithium hydroxide in a solvent such as water and/ormethanol and/or THF conveniently at ambient temperature or at elevatedtemperature (e.g., reflux) for about one hour to about five hours toprepare the Formula XXIX acid.

The Formula XXIX acid is coupled with guanidine in the presence of asuitable coupling agent as described for the above coupling of theFormula V acid and guanidine. In one embodiment, the Formula XXIX acidis activated with thionyl chloride at a temperature of about 60° C. toabout 90° C. for about fifteen minutes to about two hours. The resultingactivated acid chloride is combined with guanidine hydrochloride and aninorganic base (e.g., sodium hydroxide) in anhydrous tetrahydrofuran andoptionally methanol and/or water. The solution is heated, convenientlyat reflux, for about one hour to about eight hours to prepare theFormula XXX compound.

Alternatively according to Scheme V the Formula XXVIII compound can bedirectly converted to the Formula XXX compound by several methods. Forexample, the Formula XXVIII compound can be heated in the presence ofexcess guanidine, in a polar protic solvent for example, methanol orisopropanol at a suitable temperature conveniently, at reflux for aboutone to about seventy-two hours. This transformation may also beperformed by repeatedly removing the solvent, for example removingethanol or toluene about four times, from a mixture of the FormulaXXVIII compound and excess guanidine at a pressure of about one to about100 mmHg and at a temperature of about 25° C. to about 95° C. Thisreaction may also be performed in the absence of solvent by heating themixture of the Formula XXVIII compound and excess guanidine at atemperature of about 100° C. to about 180° C., optionally at about apressure of about 1 to about 100 mmHg for about five minutes to abouteight hours.

According to Scheme VI, the Formula XXXV compound, wherein R³ is asdescribed above, is reacted with the Formula XXXVI compound, wherein R¹and R² are as described above, in an aprotic solvent at a temperature ofabout 0° C. to about 25° C. for about two hours to about twenty-fourhours in the presence of an appropriate amine base, such astriethylamine, to form the Formula XXXVII compound.

The resulting Formula XXXVII compound is hydrolyzed and coupled withguanidine using one of the methods described in earlier Schemes, such asthe method employing carbonyidiimidazole, to form the Formula XXXVIIIcompound.

According to Scheme VII, the Formula XL hydrazine, wherein R² is asdescribed above, is reacted with the appropriate Formula XLI compound toform the Formula XLII pyrazole ester wherein R is lower alkyl accordingto the method of Bajnati, A. and Hubert-Habart, M. Bull. Soc. Chim.France 1988, 540. The resulting pyrazole ester is converted to theFormula XLIII acyl guanidine using the hydrolysis and coupling methodsdescribed above.

According to Scheme VIII, the Formula L compound wherein R² and R¹ areas described above is transformed to the Formula LI lithium salt where Ris lower alkyl according to the method described in J. Het. Chem. 1989,26, 1389. The Formula LI lithium salt is combined with the Formula LIIhydrazine, wherein R³ is as described above, in an inert solvent such asethanol, in the presence of a mineral acid, at a temperature of about20° C. to about 30° C. for about five minutes to about one hour followedby heating to a temperature of about 70° C. to about 110° C. for twohours to about four hours to form both the Formula LIII and LIVpyrazoles. The Formula LIII and LIV pyrazoles are converted to theFormula LV and LVI acyl guanidines respectively using the hydrolysis andcoupling methods described above.

Some of the methods useful for the preparation of the compoundsdescribed herein may require protection of remote functionality (e.g.,primary amine, secondary amine, carboxyl in Formula I precursors). Theneed for such protection will vary depending on the nature of the remotefunctionality and the conditions of the preparation methods. The needfor such protection is readily determined by one skilled in the art. Theuse of such protection/deprotection methods is also within the skill inthe art. For a general description of protecting groups and their use,see T. W. Greener, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991.

The starting materials and reagents for the above described compounds,are also readily available or can be easily synthesized by those skilledin the art using conventional methods of organic synthesis. For example,the aromatic hydrazines used in this invention can be prepared from thecorresponding aromatic amines by diazotization followed by reductionconveniently using stannous chloride using procedures known to thoseskilled in the art. For example, many of the compounds used herein arerelated to, or are derived from compounds found in nature, in whichthere is a large scientific interest and commercial need, andaccordingly many such compounds are commercially available or arereported in the literature or are easily prepared from other commonlyavailable substances by methods which are reported in the literature.

Some of the compounds of this invention have asymmetric carbon atoms andtherefore are enantiomers or diastereomers. Diasteromeric mixtures canbe separated into their individual diastereomers on the basis of theirphysical chemical differences by methods known per se., for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diasteromericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomers, enantiomers andmixtures thereof are considered as part of this invention. Also, some ofthe compounds of this invention are atropisomers (e.g., substitutedbiaryls) and are considered as part of this invention.

Those skilled in the art will recognize that the compounds of Formula Ican exist in several tautomeric forms. All such tautomeric forms areconsidered as part of this invention. For example, all of the tautomericforms of the carbonylguanidine moiety of the compounds of Formula I areincluded in this invention. Also, for example all enol-keto forms of thecompounds of Formula I are included in this invention.

Some of the compounds of this invention are acidic and they form a saltwith a pharmaceutically acceptable cation. All of the compounds of thisinvention are basic and they form a salt with a pharmaceuticallyacceptable anion. All such salts, including di-salts are within thescope of this invention and they can be prepared by conventionalmethods. For example, they can be prepared simply by contacting theacidic and basic entities, in either an aqueous, non-aqueous orpartially aqueous medium. The salts are recovered either by filtration,by precipitation with a non-solvent followed by filtration, byevaporation of the solvent, or, in the case of aqueous solutions, bylyophilization, as appropriate.

In addition, when the compounds of this invention form metabolites,hydrates or solvates they are also within the scope of the invention.

Other cardiovascular agents known to those skilled in the art forexample β-blockers (e.g., acebutolol, atenolol, bopindolol, labetolol,mepindolol, nadolol, oxprenol, pindolol, propranolol, sotalol), calciumchannel blockers (e.g., amlodipine, nifedipine, nisoldipine,nitrendipine, verapamil), potassium channel openers, adenosine,adenosine agoinists, ACE inhibitors (e.g., captopril, enalapril),nitrates (e.g., isosorbide dinitrate, isosorbide 5-mononitrate, glyceryltrinitrate), diuretics (e.g., hydrochlorothiazide, indapamide,piretanide, xipamide), glycosides (e.g., digoxin, metildigoxin),thrombolytics (e.g. tPA), platelet inhibitors (e.g., reopro), aspirin,dipyridamol, potassium chloride, clonidine, prazosin, aldose reductaseinhibitors (e.g., zopolrestat) and adenosine A₃ receptor agonists may beused in conjunction with the compounds of this invention.

In combination therapy treatment, both the compounds of this inventionand the other drug therapies are administered to mammals (e.g., humans,male or female) by conventional methods.

Any aldose reductase inhibitor may be used as the second compound(active agent) of this invention for combination therapies. The termaldose reductase inhibitor refers to compounds which inhibit thebioconversion of glucose to sorbitol catalyzed by the enzyme aldosereductase. Such inhibition is readily determined by those skilled in theart according to standard assays (J. Malone, Diabetes, 29:861-864, 1980.“Red Cell Sorbitol, an Indicator of Diabetic Control”). A variety ofaldose reductase inhibitors are described and referenced below, however,other aldose reductase inhibitors will be known to those skilled in theart. The disclosures of U.S. patents listed below are herebyincorporated by reference. Also, common chemical USAN names or otherdesignation are in parentheses where applicable, together with referenceto appropriate patent literature disclosing the compound.

The activity of an aldose reductase inhibitor in a tissue can bedetermined by testing the amount of aldose reductase inhibitor that isrequired to lower tissue sorbitol (i.e., by inhibiting the furtherproduction of sorbitol consequent to blocking aldose reductase) or lowertissue fructose (by inhibiting the production of sorbitol consequent toblocking aldose reductase and consequently the production of fructose).While not wishing to be bound by any particular theory or mechanism, itis believed that an aldose reductase inhibitor, by inhibiting aldosereductase, prevents or reduces ischemic damage as described hereinafter.

Accordingly, examples of aldose reductase inhibitors useful in thecompositions and methods of this invention include:

1. 3-(4-bromo-2-fluorobenzyl)-3,4-dihydro-4-oxo-1-phthalazineacetic acid(ponalrestat, U.S. Pat. No. 4,251,528);

2.N[[(5-trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl}-N-methylglycine(tolrestat, U.S. Pat. No. 4,600,724);

3. 5-[(Z,E)-β-methylcinnamylidene]-4-oxo-2-thioxo-3-thiazolideneaceticacid (epalrestat, U.S. Pat. Nos. 4,464,382, 4,791,126, 4,831,045);

4.3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineaceticacid (zenarestat, U.S. Pat. Nos. 4,734,419, and 4,883,800);

5. 2R,4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. Pat.No. 4,883,410);

6. 2R,4R-6,7-dichloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic acid(U.S. Pat. No. 4,883,410);

7. 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic acid(U.S. Pat. No. 4,771,050);

8.3,4-dihydro-3-oxo-4-[(4,5,7-trifluoro-2-benzothiazolyl)methyl]-2H-1,4-benzothiazine-2-aceticacid (SPR-210, U.S. Pat. No. 5,252,572);

9.N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-methyl-benzeneacetamide(ZD5522, U.S. Pat. Nos. 5,270,342 and 5,430,060);

10. (S)-6-fluorospiro[chroman-4,4′-imidazolidine]-2,5′-dione (sorbinil,U.S. Pat. No. 4,130,714);

11. d-2-methyl-6-fluoro-spiro(chroman4′,4′-imidazolidine)-2′,5′-dione(U.S. Pat. No. 4,540,704);

12. 2-fluoro-spiro(9H-fluorene-9,4′imidazolidine)2′,5′-dione (U.S. Pat.No. 4,438,272);

13. 2,7-di-fluoro-spiro(9H-fluorene-9,4′imidazolidine)2′,5′-dione (U.S.Pat. Nos. 4,436,745, 4,438,272);

14.2,7-di-fluoro-5-methoxy-spiro(9H-fluorene-9,4′imidazolidine)2′,5′-dione(U.S. Pat. Nos. 4,436,745, 4,438,272);

15. 7-fluoro-spiro(5H-indenol[1,2-b]pyridine-5,3′-pyrrolidine)2,5′-dione(U.S. Pat. Nos. 4,436,745, 4,438,272);

16.d-cis-6′-chloro-2′,3′-dihydro-2′-methyl-spiro-(imidazolidine-4,4′-4′-H-pyrano(2,3-b)pyridine)-2,5-dione (U.S. Pat. No. 4,980,357);

17.spiro[imidazolidine-4,5′(6H)-quinoline]2,5-dione-3′-chloro-7′,8′-dihydro-7′-methyl-(5′-cis)(U.S. Pat. No. 5,066,659);

18.(2S,4S)-6-fluoro-2′,5′-dioxospiro(chroman-4,4′-imidazolidine)-2-carboxamide(U.S. Pat. No. 5,447,946); and

19.2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H),3′-pyrrolidine]-1,2′,3,5′(2H)-tetrone(ARI-509, U.S. Pat. No. 5,037,831).

Other aldose reductase inhibitors include compounds having formula IB

or a pharmaceutically acceptable salt thereof, wherein

Z is O or S;

R¹ is hydroxy or a group capable of being removed in vivo to produce acompound of formula IB wherein R¹ is OH; and

X and Y are the same or different and are selected from hydrogen,trifluornomethyl, fluoro, and chloro.

A preferred subgroup within the above group of aldose reductaseinhibitors includes numbered compounds 1, 2, 3, 4, 5, 6, 9, 10, and 17,and the following compounds of Formula IB:

20.3,4-dihydro-3-(5-fluorobenzothiazol-2-ylmethyl)-4oxophthalazin-1-yl-aceticacid [R¹=hydroxy; X=F; Y=H];

21.3-(5,7-difluorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Y=F];

22.3-(5-chlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Cl; Y=H];

23.3-(5,7-dichlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Y=Cl];

24.3,4-dihydro-4-oxo-3-(5-trifluoromethylbenzoxazol-2-ylmethyl)phthalazin-1-ylaceticacid [R¹=hydroxy; X=CF₃; Y=H];

25.3,4-dihydro-3-(5-fluorobenzoxazol-2-ylmethyl)-4-oxophthalazin-1-yl-aceticacid [R¹=hydroxy; X=F; Y=H];

26.3-(5,7-difluorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Y=F];

27.3-(5-chlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Cl; Y=H];

28.3-(5,7-dichlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Y=Cl]; and

29. zopolrestat; 1-phthalazineacetic acid,3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-[R¹=hydroxy;X=trifluoromethyl; Y=H].

In compounds 20-23, and 29 Z is S. In compounds 24-28, Z is O.

Of the above subgroup, compounds 20-29 are more preferred with 29especially preferred.

An especially preferred aldose reductase inhibitor is1-phthalazineacetic acid,3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]-.

The aldose reductase inhibitor compounds of this invention are readilyavailable or can be easily synthesized by those skilled in the art usingconventional methods of organic synthesis, particularly in view of thepertinent patent specification descriptions.

An amount of the aldose reductase inhibitor of this invention that iseffective for the activities of this invention may be used. Typically,an effective dosage for the aldose reductase inhibitors of thisinvention is in the range of about 0.1 mg/kg/day to 100 mg/kg/day insingle or divided doses, preferably 0.1 mg/kg/day to 20 mg/kg/day insingle or divided doses.

Any glycogen phosphorylase inhibitor may be used as the second compoundof this invention. The term glycogen phosphorylase inhibitor refers toany substance or agent or any combination of substances and/or agentswhich reduces, retards, or eliminates the enzymatic action of glycogenphosphorylase. The currently known enzymatic action of glycogenphosphorylase is the degradation of glycogen by catalysis of thereversible reaction of a glycogen macronmolecule and inorganic phosphateto glucose-1-phosphate and a glycogen macromolecule which is oneglucosyl residue shorter than the original glycogen macromolecule(forward direction of glycogenolysis). Such actions are readilydetermined by those skilled in the art according to standard assays(e.g., as described hereinafter). A variety of these compounds areincluded in the following published international patent applications:PCT application publication WO 96/39384 and WO96/39385.However, otherglycogen phosphorylase inhibitors will be known to those skilled in theart.

Preferred glycogen phosphorylase inhibitors include compounds having theFormula IC

and the pharmaceutically acceptable salts and prodrugs thereof

wherein

the dotted line (---) is an optional bond;

A is —C(H)═, —C((C₁-C₄)alkyl)═ or —C(halo)═ when the dotted line (---)is a bond, or A is methylene or —CH((C₁-C₄)alkyl)— when the dotted line(---) is not a bond;

R₁, R₁₀ or R₁₁ are each independently H, halo, 4-, 6- or 7-nitro, cyano,(C₁-C₄)alkyl, (C₁-C₄)alkoxy, fluoromethyl, difluoromethyl ortrifluoromethyl;

R₂ is H;

R₃ is H or (C₁-C₅)alkyl;

R⁴ is H, methyl, ethyl, n-propyl, hydroxy(C₁-C₃)alkyl,(C₁-C₃)alkoxy(C₁-C₃)alkyl, phenyl(C₁-C₄)alkyl,phenylhydroxy(C₁-C₄)alkyl, phenyl(C₁-C₄)alkoxy(C₁-C₄)alkyl, thien-2- or-3-yl(C₁-C₄)alkyl or fur-2- or -3-yl(C₁-C₄)alkyl wherein said R₄ ringsare mono-, di- or tri-substituted independently on carbon with H, halo,(C₁-C₄)alkyl, (C₁-C₄)alkoxy, trifluoromethyl, hydroxy, amino or cyano;or

R₄ is pyrid-2-, -3- or -4-yl(C₁-C₄)alkyl, thiazol-2-, -4- or-5-yl(C₁-C₄)alkyl, imidazol -1-, -2-, -4- or -5-yl(C₁-C₄)alkyl,pyrrol-2- or -3-yl(C₁-C₄)alkyl, oxazol-2-, -4- or -5-yl-(C₁-C₄)alkyl,pyrazol-3-, 4- or -5-yl(C₁-C₄)alkyl, isoxazol-3-, -4- or-5-yl(C₁-C₄)alkyl, isothiazol-3-, -4- or -5-yl(C₁-C₄)alkyl, pyridazin-3-or -4-yl-(C₁-C₄)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C₁-C₄)alkyl,pyrazin-2- or -3-yl(C₁-C₄))alkyl or 1,3,5-triazin-2-yl(C₁-C₄)alkyl,wherein said preceding R₄ heterocycles are optionally mono- ordi-substituted independently with halo, trifluoromethyl, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, amino or hydroxy and said mono- or di-substituents arebonded to carbon;

R₅ is H, hydroxy, fluoro, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₁-C₆)alkanoyl,amino(C₁-C₄)alkoxy, mono-N— or di-N,N—(C₁-C₄)alkylamino(C₁-C₄)alkoxy,carboxy(C₁-C₄)alkoxy, (C₁-C₅)alkoxy-Carbonyl(C₁-C₄)alkoxy,benzyloxycarbonyl(C₁-C₄)alkoxy, or carbonyloxy wherein said carbonyloxyis carbon-carbon linked with phenyl, thiazolyl, imidazolyl, 1H-indolyl,furyl, pyrrolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl and wherein saidpreceding R₅ rings are optionally mono-substituted with halo,(C₁-C₄)alkyl, (C₁-C₄)alkoxy, hydroxy, amino or trifluoromethyl and saidmono-substituents are bonded to carbon;

R₇ is H, fluoro or (C₁-C₅)alkyl; or

R₅ and R₇ can be taken together to be oxo;

R₆ is carboxy, (C₁-C₈)alkoxycarbonyl, C(O)NR₈R₉ or C(O)R₁₂, wherein

R₈ is H, (C₁-C₃)alkyl, hydroxy or (C₁-C₃)alkoxy; and

R₉ is H, (C₁-C₈)alkyl, hydroxy, (C₁-C₈)alkoxy,methylene-perfluorinated(C₁-C₈)alkyl, phenyl, pyridyl, thienyl, furyl,pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl,piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl,piperazinyl or 1,3,5-triazinyl wherein said preceding R₉ rings arecarbon-nitrogen linked; or

R₉ is mono-, di- or tri-substituted (C₁-C₅)alkyl, wherein saidsubstituents are independently H, hydroxy, amino, mono-N— ordi-N,N—(C₁-C₅)alkylamino; or

R₉ is mono- or di-substituted (C₁-C₅)alkyl, wherein said substituentsare independently phenyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,isoxazolyl, isothiazolyl, pyranyl, pyridinyl, piperidinyl, morpholinyl,pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl or 1,3,5-triazinyl

wherein the nonaromatic nitrogen-Containing R₉ rings are optionallymono-substituted on nitrogen with (C₁-C₆)alkyl, benzyl, benzoyl or(C₁-C₆)alkoxycarbonyl and wherein the R₉ rings are optionallymono-substituted on carbon with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,hydroxy, amino, or mono-N— and di-N,N (C₁-C₅)alkylamino provided that noquaternized nitrogen is included and there are no nitrogen-oxygen,nitrogen-nitrogen or nitrogen-halo bonds;

R₁₂ is piperazin-1-yl, 4-(C₁-C₄)alkylpiperazin-1-yl,4-formylpiperazin-1-yl, morpholino, thiomorpholino, 1-oxothiomorpholino,1,1-dioxo-thiomorpholino, thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl,1,1-dioxo-thiazolidin-3-yl, 2-(C₁-C₆)alkoxycarbonylpyrrolidin-1-yl,oxazolidin-3-yl or 2(R)-hydroxymethylpyrrolidin-1-yl; or

R₁₂ is 3- and/or 4-mono- or di-substituted oxazetidin-2-yl, 2-, 4-,and/or 5-mono- or di-substituted oxazolidin-3-yl, 2-, 4-, and/or 5-mono- or di-substituted thiazolidin-3-yl, 2-, 4-, and/or 5- mono- ordi-substituted 1-oxothiazolidin-3-yl, 2-, 4-, and/or 5-mono- ordi-substituted 1,1-dioxothiazolidin-3-yl, 3- and/or 4-, mono- ordi-substituted pyrrolidin-1-yl, 3-, 4- and/or 5-, mono-, di- ortri-substituted piperidin-1-yl, 3-, 4-, and/or 5-mono-, di-, ortri-substituted piperazin-1-yl, 3-substituted azetidin-1-yl, 4- and/or5-, mono- or di-substituted 1,2-oxazinan-2-yl, 3-and/or 4-mono- ordi-substituted pyrazolidin-1-yl, 4- and/or 5-, mono- or di-substitutedisoxazolidin-2-yl, 4- and/or 5-, mono- and/or di-substitutedisothiazolidin-2-yl wherein said R₁₂ substituents are independently H,halo, (C₁-C₅)-alkyl, hydroxy, amino, mono-N— ordi-N,N—(C₁-C₅)alkylamino, formyl, oxo, hydroxyimino, (C₁-C₅)alkoxy,carboxy, carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl,(C₁-C₄)alkoxyimino, (C₁-C₄)alkoxymethoxy, (C₁-C₆)alkoxycarbonyl,carboxy(C₁-C₅)alkyl or hydroxy(C₁-C₅)alkyl;

with the proviso that if R⁴ is H, methyl, ethyl or n-propyl R₅ is OH;

with the proviso that if R₅ and R₇ are H, then R⁴ is not H, methyl,ethyl, n-propyl, hydroxy(C₁-C₃)alkyl or (C₁-C₃)alkoxy(C₁-C₃)alkyl and R₆is C(O)NR₈R₉, C(O)R₁₂ or (C₁-C₄)alkoxycarbonyl.

Preferred glycogen phosphorylase inhibitors include compounds having theFormula ID

and the pharmaceutically acceptable salts and prodrugs thereof

wherein

the dotted line (---) is an optional bond;

A is —C(H)═, —C((C₁-C₄)alkyl)═, —C(halo)═ or —N═, when the dotted line(---) is a bond, or A is methylene or —CH((C₁-C₄)alkyl)-, when thedotted line (---) is not a bond;

R₁, R₁₀ or R₁₁ are each independently H, halo, cyano, 4-, 6-, or7-nitro, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, fluoromethyl, difluoromethyl ortrifluoromethyl;

R₂ is H;

R₃ is H or (C₁-C₅)alkyl;

R⁴ is H, methyl, ethyl, n-propyl, hydroxy(C₁-C₃)alkyl,(C₁-C₃)alkoxy(C₁-C₃)alkyl, phenyl(C₁-C₄)alkyl,phenylhydroxy(C₁-C₄)alkyl, (phenyl)((C₁-C₄)-alkoxy)(C₁-C₄)alkyl,thien-2- or -3-yl(C₁-C₄)alkyl or fur-2- or -3-yl(C₁-C₄)alkyl wherein,said R⁴ rings are mono-, di- or tri-substituted independently on carbonwith H, halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, trifluoromethyl, hydroxy,amino, cyano or 4,5-dihydro-1H-imidazol-2-yl; or

R₄ is pyrid-2-, -3- or 4-yl(C₁-C₄)alkyl, thiazol-2-, 4- or-5-yl(C₁-C₄)alkyl, imidazol-2-, -4- or -5-yl(C₁-C₄)alkyl, pyrrol-2- or-3-yl(C₁-C₄)alkyl, oxazol-2-, -4- or -5-yl(C₁-C₄)alkyl, pyrazol-3-, -4-or -5-yl(C₁-C₄)alkyl, isoxazol-3-, -4- or -5-yl(C₁-C₄)alkyl,isothiazol-3-, -4- or -5-yl(C₁-C₄)alkyl, pyridazin-3- or-4-yl(C₁-C₄)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C₁-C₄)alkyl,pyrazin-2- or -3-yl(C₁-C₄)alkyl, 1,3,5-triazin-2-yl(C₁-C₄)alkyl orindol-2-(C₁-C₄)alkyl, wherein said preceding R⁴ heterocycles areoptionally mono- or di-substituted independently with halo,trifluoromethyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, amino, hydroxy or cyanoand said substituents are bonded to carbon; or

R⁴ is R₁₅-carbonyloxymethyl, wherein said R₁₅ is phenyl, thiazolyl,imidazolyl, 1H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinylor 1,3,5-triazinyl and wherein said preceding R₁₅ rings are optionallymono- or di-substituted independently with halo, amino, hydroxy,(C₁-C₄)alkyl, (C₁-C₄)alkoxy or trifluoromethyl and said mono- ordi-substituents are bonded to carbon;

R₅ is H;

R₆ is carboxy, (C₁-C₈)alkoxycarbonyl, benzyloxycarbonyl, C(O)NR₈R₉ orC(O)R₁₂ wherein

R₈ is H, (C₁-C₆)alkyl, cyclo(C₃-C₆)alkyl, cyclo(C₃-C₆)alkyl(C₁-C₅)alkyl,hydroxy or (C₁-C₈)alkoxy; and

R₉ is H, cyclo(C₃-C₈)alkyl, cyclo(C₃-C₈)alkyl(C₁-C₅)alkyl,cyclo(C₄-C₇)alkenyl, cyclo(C₃-C₇)alkyl(C₁-C₅)alkoxy,cyclo(C₃-C₇)alkyloxy, hydroxy, methylene-perfluorinated(C₁-C₈)alkyl,phenyl, or a heterocycle wherein said heterocycle is pyridyl, furyl,pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl,pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, benzothiazolyl, benzoxazolyl,benzimidazolyl, thiochromanyl or tetrahydrobenzothiazolyl wherein saidheterocycle rings are carbon-nitrogen linked; or

R₉ is (C₁-C₆)alkyl or (C₁-C₈)alkoxy wherein said (C₁-C₆)alkyl or(C₁-C₈)alkdxy is optionally monosubstituted with cyclo(C₄-C₇)alken-1-yl,phenyl, thienyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl,thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl,pyridazinyl, pyrmidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl orindolyl and wherein said (C₁-C₆)alkyl or (C₁-C₈)alkoxy are optionallyadditionally independently mono- or di-substituted with halo, hydroxy,(C₁-C₅)alkoxy, amino, mono-N— or di-N,N—(C₁-C₅)alkylamino, cyano,carboxy, or (C₁-C₄)alkoxycarbonyl; and

wherein the R₉ rings are optionally mono- or di-substitutedindependently on carbon with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, hydroxy,hydroxy(C₁-C₄)alkyl, amino(C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, cyano, carboxy,(C₁-C₅)alkoxycarbonyl, carbamoyl, formyl or trifluoromethyl and said R₉rings may optionally be additionally mono- or di-substitutedindependently with (C₁-C₅)alkyl or halo;

with the proviso that no quaternized nitrogen on any R₉ heterocycle isincluded;

R₁₂ is morpholino, thiomorpholino, 1-oxothiomorpholino,1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl,1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl,piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl,pyrazolidin-1-yl, isoxazolidin-2-yl, isothiazolidin-2-yl,1,2-oxazetidin-2-yl, oxazolidin-3-yl, 3,4-dihydroisoquinolin-2-yl,1,3-dihydroisoindol-2-yl, 3,4-dihydro-2H-quinol-1-yl,2,3-dihydro-benzo[1,4]oxazin-4-yl, 2,3-dihydro-benzo[1,4]-thiazine-4-yl,3,4-dihydro-2H-quinoxalin-1-yl, 3,4-dihydro-benzo[c][1,2]oxazin-1-yl,1,4-dihydro-benzo[d][1,2]oxazin-3-yl,3,4-dihydro-benzo[e][1,2]-oxazin-2-yl, 3H-benzo[d]isoxazol-2-yl,3H-benzo[c]isoxazol-1-yl or azepan-1-yl,

wherein said R₁₂ rings are optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, hydroxy, amino,mono-N— or di-N,N—(C₁-C₅)alkylamino, formyl, carboxy, carbamoyl, mono-N—or di-N,N—(C₁-C₅)alkylcarbamoyl, (C₁-C₆)alkoxy(C₁-C₃)alkoxy,(C₁-C₅)alkoxycarbonyl, benzyloxycarbonyl,(C₁-C₅)alkoxycarbonyl(C₁-C₅)alkyl, (C₁-C₄)alkbxycarbonylamino,carboxy(C₁-C₅)alkyl, carbamoyl(C₁-C₅)alkyl, mono-N— ordi-N,N—(C₁-C₅)alkylcarbamoyl(C₁-C₅)alkyl, hydroxy(C₁-C₅)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, amino(C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino(C₁-C₄)alkyl, oxo, hydroxyimino or(C₁-C₆)alkoxyimino and wherein no more than two substituents areselected from oxo, hydroxyimino or (C₁-C₆)alkoxyimino and oxo,hydroxyimino or (C₁-C₆)alkoxyimino are on nonaromatic carbon; and

wherein said R₁₂ rings are optionally additionally mono- ordi-substituted independently with (C₁-C₅)alkyl or halo;

with the proviso that when R₆ is (C₁-C₅)alkoxycarbonyl orbenzyloxycarbonyl then R₁ is 5-halo, 5-(C₁-C₄)alkyl or 5-cyano and R⁴ is(phenyl)(hydroxy)(C₁-C₄)alkyl, (phenyl)((C₁-C₄)alkoxy)(C₁-C₄)alkyl,hydroxymethyl or Ar(C₁-C₂)alkyl, wherein Ar is thien-2- or -3-yl, fur-2-or -3-yl or phenyl wherein said Ar is optionally mono- or di-substitutedindependently with halo; with the provisos that when R₄ is benzyl and R₅is methyl, R₁₂ is not -4-hydroxy-piperidin-1-yl or when R₄ is benzyl andR₅ is methyl R₆ is not C(O)N(CH₃)₂;

with the proviso that when R₁ and R₁₀ and R₁₁ are H, R₄ is notimidazol4-ylmethyl, 2-phenylethyl or 2-hydroxy-2-phenylethyl;

with the proviso that when both R₈ and R₉ are n-pentyl, R₁ is 5-chloro,5-bromo, 5-cyano, 5(C₁-C₅)alkyl, 5(C₁-C₅)alkoxy or trifluoromethyl;

with the proviso that when R₁₂ is 3,4-dihydroisoquinol-2-yl, said3,4-dihydroisoquinol-2-yl is not substituted with carboxy((C₁-C₄)alkyl;

with the proviso that when R₈ is H and R₉ is (C₁-C₆)alkyl, R₉ is notsubstituted with carboxy or (C₁-C₄)alkoxycarbonyl on the carbon which isattached to the nitrogen atom N of NHR₉; and

with the proviso that when R₆ is carboxy and R₁, R₁₀, R₁₁ and R₅ are allH, then R₄ is not benzyl, H, (phenyl)(hydroxy)methyl, methyl, ethyl orn-propyl.

In general an effective dosage for the pharmacological combinationcompositions of this invention, for example the ischemic damage reducingactivities of combinations containing the glycogen phosphorylaseinhibitor compounds of this invention, is in the range of 0.005 to 50mg/kg/day, preferably 0.01 to 25 mg/kg/day and most preferably 0.1 to 15mg/kg/day.

The compounds of the present invention inhibit the sodium/proton(Na+/H+) exchange transport system and hence are useful as a therapeuticor prophylactic agent for diseases caused or aggravated by theacceleration of the sodium/proton (Na+/H+) exchange transport system,for example, cardiovascular diseases [e.g., arteriosclerosis,hypertension, arrhythmia (e.g. ischemic arrhythmia, arrhythmia due tomyocardial infarction, myocardial stunning, myocardial dysfunction,arrhythmia after PTCA or after thrombolysis, etc.), angina pectoris,cardiac hypertrophy, myocardial infarction, heart failure (e.g.congestive heart failure, acute heart failure, cardiac hypertrophy,etc.), restenosis after PTCA, PTCI, shock (e.g. hemorrhagic shock,endotoxin shock, etc.)], renal diseases (e.g. diabetes mellitus,diabetic nephropathy, ischemic acute renal failure, etc.) organdisorders associated with ischemia or ischemic reperfusion [(e.g. heartmuscle ischemic reperfusion associated disorders, acute renal failure,or disorders induced by surgical treatment such as coronary arterybypass grafting (CABG) surgeries, vascular surgeries, organtransplantation, non-Cardiac surgeries or percutaneous transluminalcoronary angioplasty (PTCA)], cerebrovascular diseases (e.g. ischemicstroke, hemorrhagic stroke, etc.), cerebro ischemic disorders (e.g.disorders associated with cerebral infarction, disorders caused aftercerebral apoplexy as sequelae, or cerebral edema. The compounds of thisinvention can also be used as an agent for myocardial protection duringcoronary artery bypass grafting (CABG) surgeries, vascular surgeries,percutaneous transluminal coronary angioplasty (PTCA), PTCI, organtransplantation, or non-Cardiac surgeries.

Preferably, the compounds of this invention can be used as agents formyocardial protection before, during, or after coronary artery bypassgrafting (CABG) surgeries, vascular surgeries, percutaneous transluminalcoronary angioplasty (PTCA), organ transplantation, or nonrdiacsurgeries.

Preferably, the compounds of this invention can be used as agents formyocardial protection in patients presenting with ongoing cardiac (acutecoronary syndromes, e.g. myocardial infarction or unstable angina) orcerebral ischemic events (e.g. stroke).

Preferably, the compounds of this invention can be used as agents forchronic myocardial protection in patients with diagnosed coronary heartdisease (e.g. previous myocardial infarction or unstable angina) orpatients who are at high risk for myocardial infarction (age greaterthan 65 and two or more risk factors for coronary heart disease).

In addition to this, the compounds of this invention are notable fortheir strong inhibitory effect on the proliferation of cells, forexample the proliferation of fibroblast cells and the proliferation ofthe smooth muscle cells of the blood vessels. For this reason, thecompounds of this invention are valuable therapeutic agents for use indiseases in which cell proliferation represents a primary or secondarycause and may, therefore, be used as antiatherosclerotic agents, and asagents against diabetic late complications, cancerous diseases, fibroticdiseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis,glomerular nephrosclerosis, organ hypertrophies or hyperplasias, inparticular hyperplasia or hypertrophy of the prostate, pulmonaryfibrosis, diabetic complications or recurrent stricture after PTCA, ordiseases caused by endothelial cell injury.

The utility of the compounds of the present invention as medical agentsin the treatment of diseases, such as are detailed herein in mammals(e.g. humans) for example, myocardial protection during surgery ormycardial protection in patients presenting with ongoing cardiac orcerebral ischemic events or chronic cardioprotection in patients withdiagnosed coronary heart disease, or at risk for coronary heart disease,cardiac dysfunction or myocardial stunning is demonstrated by theactivity of the compounds of this invention in conventional preclinicalcardioprotection assays [see the in vivo assay in Klein, H. et al.,Circulation 92:912-917 (1995); the isolated heart assay in Scholz, W. etal., Cardiovascular Research 29:260-268 (1995); the antiarrhythmic assayin Yasutake M. et al., Am. J. Physiol., 36:H2430-H2440 (1994); the NMRassay in Kolke et al., J. Thorac. Cardiovasc. Surg. 112: 765-775 (1996)]and the additional in vitro and in vivo assays described below. Suchassays also provide a means whereby the activities of the compounds ofthis invention can be compared with the activities of other knowncompounds. The results of these comparisons are useful for determiningdosage levels in mammals, including humans, for the treatment of suchdiseases.

Measurement of Human NHE-1 Inhibitory Activity

Methodologies for measurement of human NHE-1 activity and inhibitorpotency are based on those published by Watson et al., Am. J. Physiol.,24:G229-G238, 1991), where NHE-mediated recovery of intracellular pH ismeasured following intracellular acidification. Thus, fibroblasts stablyexpressing human NHE-1 (Counillon, L. et al., Mol. Pharmacol.,44:1041-1045 (1993) are plated onto collagen coated 96 well plates(50,000/well) and grown to confluence in growth media (DMEM highglucose, 10% fetal bovine serum, 50 u/ml penicillin and streptomycin).Confluent plates are incubated for 30 min at 37° C. with the pHsensitive fluorescent probe BCECF (5 μM; Molecular Probes, Eugene,Oreg.). BCECF loaded cells are incubated for 30 min at 37° C. in acidloading media (70 mM choline chloride, 50 mM NHCl₄, 5 mM KCl, 1 mMMgCl₂, 1.8 mM CaCl₂, 5 mM glucose, 10 mM HEPES, pH 7.5), and then placedin a Fluorescent Imaging Plate Reader (Molecular Devices, CA). BCECFfluorescence is monitored using excitation and emission wavelengths of485 nM and 525 nM, respectively. Intracellular acidification isinitiated via rapid replacement of acid loading media with recoverymedia (120 mM NaCl, 5 mM KCl, 1 mM MgCl₂, 1.8 mM CaCl₂, 5 mM glucose, 10mM HEPES, pH 7.5)±test compound, and NHE-mediated recovery ofintracellular pH is monitored as the subsequent time-dependent increaseBCECF fluorescence. The potency of human NHE-1 inhibitors is calculatedas the concentration that reduces recovery of intracellular pH by 50%(IC₅₀). Under these conditions reference NHE inhibitors amiloride andHOE-642 had IC₅₀ values for human NHE-1 of 50 μM and 0.5 μM,respectively.

As background information, it is noted that brief periods of myocardialischemia followed by coronary artery reperfusion protects the heart fromsubsequent severe myocardial ischemia (Murry et al., Circulation74:1124-1136, 1986).

The therapeutic effects of the compounds of this invention in preventingheart tissue damage resulting from an ischemic insult can bedemonstrated in vitro along lines presented in Liu et al. (Cardiovasc.Res., 28:1057-1061, 1994), as described specifically herein.Cardioprotection, as indicated by a reduction in infarcted myocardium,can be induced pharmacologically using adenosine receptor agonists inisolated, retrogradely perfused rabbit hearts as an in vitro model ofmyocardial ischemic preconditioning (Liu et al., Cardiovasc. Res.,28:1057-1061, 1994). The in vitro test described below demonstrates thata test compound (i.e., a compound as claimed herein) can alsopharmacologically induce cardioprotection, i.e., reduced myocardialinfarct size, when administered to a rabbit isolated heart. The effectsof the test compound are compared to ischemic preconditioning and theA1/A3 adenosine agonist, APNEA (N⁶-[2-(4-aminophenyl)ethyl]adenosine),that has been shown to pharmacologically induce cardioprotection in therabbit isolated heart (Liu et al., Cardiovasc. Res., 28:1057-1061,1994). The exact methodology is described below.

The protocol used for these experiments closely follows that describedby Liu et al., Cardiovasc. Res., 28:1057-1061, 1994. Male New ZealandWhite rabbits (3-4 kg) are anesthetized with sodium pentobarbital (30mg/kg, i.v.). After deep anesthesia is achieved (determined by theabsence of an ocular blink reflex) the animal is intubated andventilated with 100% O₂ using a positive pressure ventilator. A leftthoracotomy is performed, the heart exposed, and a snare (2-0 silk) isplaced loosely around a prominent branch of the left coronary artery,approximately ⅔ of the distance towards the apex of the heart. The heartis removed from the chest and rapidly (<30 sec) mounted on a Langendorffapparatus. The heart is retrogradely perfused in a non-recirculatingmanner with a modified Krebs solution (NaCl 118.5 mM, KCl 4.7 mM, Mg SO₄1.2 mM, KH₂PO₄ 1.2 mM, NaHCO₃ 24.8 mM, CaCl₂ 2.5 mM, and glucose 10 mM),at a constant pressure of 80 mmHg and a temperature of 37° C. PerfusatepH is maintained at 7.4-7.5 by bubbling with 95% O₂/5% CO₂. Hearttemperature is tightly controlled by using heated reservoirs for thephysiological solution and water jacketing around both the perfusiontubing and the isolated heart. Heart rate and left ventricular pressuresare determined via a latex balloon which is inserted in the leftventricle and connected by stainless steel tubing to a pressuretransducer. The intraventricular balloon is inflated to provide asystolic pressure of 80-100 mmHg, and a diastolic pressure ≦10 mmHg.Total coronary flow is also continuously monitored using an in-line flowprobe and normalized for heart weight.

The heart is allowed to equilibrate for 30 min, over which time theheart must show stable left ventricular pressures within the parametersoutlined above. If the heart rate falls below 180 bpm at any time priorto the 30 min period of regional ischemia, the heart is paced at about200 bpm for the remainder of the experiment. Ischemic preconditioning isinduced by total cessation of cardiac perfusion (global ischemia) for 5min, followed by reperfusion for 10 min. The regional ischemia isprovided by tightening the snare around the coronary artery branch.Following the 30 min regional ischemia, the snare is released and theheart reperfused for an additional 120 min.

Pharmacological cardioprotection is induced by infusing the testcompound at predetermined concentrations, starting 30 min prior to the30 min regional ischemia, and continuing until the end of the 120 minreperfusion period. Hearts which receive test compounds do not undergothe period of ischemic preconditioning. The reference compound, APNEA(500 nM) is perfused through hearts (which do not receive the testcompound) for a 5 min period which ends 10 min before the 30 minregional ischemia.

At the end of the 120 min reperfusion period, the coronary artery snareis tightened, and a 0.5% suspension of fluorescent zinc cadmium sulfateparticles (1-10 μM) Duke Scientific Corp. (Palo Alto, Calif.) isperfused through the heart; this stains all of the myocardium, exceptthat area-at-risk for infarct development (area-at-risk). The heart isremoved from the Langendorff apparatus, blotted dry, wrapped in aluminumfoil and stored overnight at −20° C. The next day, the heart is slicedinto 2 mm transverse sections from the apex to the top of theventricles. The slices are stained with 1% triphenyl tetrazoliumchloride (TTC) in phosphate-buffered saline for 20 min at 37° C. SinceTTC reacts with living tissue (containing NAD-dependent dehydrogenase),this stain differentiates between living (red stained) tissue, and deadtissue (unstained infarcted tissue). The infarcted area (no stain) andthe area-at-risk (no fluorescent particles) are calculated for eachslice of left ventricle using a precalibrated image analyzer. Tonormalize the ischemic injury for differences in the area-at-riskbetween hearts, the data is expressed as the ratio of infarct area vs.area-at-risk (%IA/AAR). All data are expressed as mean±SE and comparedstatistically using a Mann-Whitney non-parametric test with a Bonferronicorrection for multiple comparisons. Significance is considered asp<0.05.

The results from the above in vitro test demonstrate that compounds ofthis invention induce significant cardioprotection relative to thecontrol group.

The therapeutic effects of the compounds of this invention in preventingheart tissue damage otherwise resulting from an ischemic insult can alsobe demonstrated in vivo along lines presented in Liu et al.(Circulation, Vol. 84:350-356, 1991) as described specifically herein.The in vivo assay tests the cardioprotection of the test compoundrelative to the control group which receives saline vehicle.Cardioprotection, as indicated by a reduction in infarcted myocardium,can be induced pharmacologically using intravenously administeredadenosine receptor agonists in intact, anesthetized rabbits studied asan in situ model of myocardial ischemic preconditioning (Liu et al.,Circulation 84:350-356, 1991). The in vivo assay tests whether compoundscan pharmacologically induce cardioprotection, i.e., reduced myocardialinfarct size, when parenterally administered to intact, anesthetizedrabbits. The effects of the compounds of this invention can be comparedto ischemic preconditioning using the A1 adenosine agonist,N⁶-1-(phenyl-2R-isopropyl) adenosine (PIA) that has been shown topharmacologically induce cardioprotection in intact anesthetized rabbitsstudied in situ (Liu et al., Circulation 84:350-356, 1991). Themethodology is described below.

Surgery: New Zealand White male rabbits (3-4 kg) are anesthetized withsodium pentobarbital (30 mg/kg, i.v.). A tracheotomy is performed via aventral midline cervical incision and the rabbits are ventilated with100% oxygen using a positive pressure ventilator. Catheters are placedin the left jugular vein for drug administration and in the left carotidartery for blood pressure measurements. The hearts are then exposedthrough a left thoracotomy and a snare (00 silk) placed around aprominent branch of the left coronary artery. Ischemia is induced bypulling the snare tight and clamping it in place. Releasing the snareallows the affected area to reperfuse. Myocardial ischemia is evidencedby regional cyanosis; reperfusion is evidenced by reactive hyperemia.

Protocol: Once arterial pressure and heart rate have been stable for atleast 30 minutes the test is started. Ischemic preconditioning isinduced by occluding the coronary artery for 5 min followed by a 10 minreperfusion. Pharmacological preconditioning is induced by infusing testcompound over, for example 5 minutes and allowing 10 minutes beforefurther intervention or by infusing the adenosine agonist, PIA (0.25mg/kg). Following ischemic preconditioning, pharmacologicalpreconditioning or no conditioning (unconditioned, vehicle control) theartery is occluded for 30 minutes and then reperfused for two hours toinduce myocardial infarction. The test compound and PIA are dissolved insaline or other suitable vehicle and delivered at 1 to 5 mg/kg,respectively.

Staining (Liu et al., Circulation 84:350-356, 1991): At the end of the 2hour reperfusion period, the hearts are quickly removed, hung on aLangendorff apparatus, and flushed for 1 minute with normal salineheated to body temperature (38° C.). The silk suture used as the snareis then tied tightly to reocclude the artery and a 0.5% suspension offluorescent zinc cadmium sulphate particles (1-10 μm) Duke ScientificCorp. (Palo Alto, Calif.) is infused with the perfusate to stain all ofthe myocardium except the area at risk (nonfluorescent ventricle). Thehearts are then quickly frozen and stored overnight at −20° C. On thefollowing day, the hearts are cut into 2 mm slices and stained with 1%triphenyl tetrazolium chloride (TTC). Since TTC reacts with livingtissue, this stain differentiates between living (red stained) tissue,and dead tissue (unstained infarcted tissue). The infarcted area (nostain) and the area at risk (no fluorescent particles) are calculatedfor each slice of left ventricle using a pre-calibrated image analyzer.To normalize the ischemic injury for differences in the area at riskbetween hearts, the data is expressed as the ratio of infarct area vs.area at risk (%IA/AAR). All data are expressed as Mean±SEM and comparedstatistically using single factor ANOVA or Mann Whitney non parametrictest. Significance is considered as p<0.05.

The compounds of this invention can be tested for their utility inreducing or preventing ischemic injury in non-cardiac tissues, forexample, the brain, or the liver, utilizing procedures reported in thescientific literature. The compounds of this invention in such tests canbe administered by the preferred route and vehicle of administration andat the preferred time of administration either prior to the ischemicepisode, during the ischemic episode, following the ischemic episode(reperfusion period) or during any of the below-mentioned experimentalstages.

The benefit of the invention to reduce ischemic brain damage can bedemonstrated, for example, in mammals using the method of Park, et al(Ann. Neurol. 1988;24:543-551). According to the procedure of Park, etal., adult male Sprague Dawley rats are anesthetized initially with 2%halothane, and thereafter by mechanical ventilation with a nitrousoxide-oxygen mixture (70%:30%) containing 0.5-1% halothane. Atracheostomy is then performed. The stroke volume of the ventilator isadjusted to maintain arterial carbon dioxide tension at approximately 35mm Hg and adequate arterial oxygenation (PaO₂>90 mm Hg). Bodytemperature can be monitored by a rectal thermometer, and the animalscan be maintained normothermic, if necessary, by external heating. Theanimals next undergo subtemporal craniectomy to expose the main trunk ofthe left middle cerebral artery (MCA) under an operating microscope, andthe exposed artery is occluded with microbipolar coagulation to generatelarge ischemic lesions in the cerebral cortex and basal ganglia. Afterthree hours of MCA occlusion, the rats are deeply anesthetized with 2%halothane and a thoracotomy is performed to infuse heparinized salineinto the left ventricle. The effluent is collected via an incision ofthe right atrium. The saline washout is followed by approximately 200 mlof a 40% formaldehyde, glacial acetic acid and absolute methanolsolution (FAM; 1:1:8, v/v/v), then the animals are decapitated and thehead is stored in fixative for 24 hours. The brain is then removed,dissected, embedded in paraffin wax, and sectioned (approximately 100sections 0.2 mm per brain). The sections are then stained withhematoxylin-eosin or with a combination of cresyl violet and Luxol fastblue, and examined by light microscopy to identify and quantitate theischemic damage using a precalibrated image analyzer. The ischemicvolumes and areas are expressed in absolute units (mm³ and mm²) and as apercentage of the total region examined. The effect of the compositionsand methods of this invention to reduce ischemic brain damage induced byMCA occlusion is noted based on a reduction in the area or volume ofrelative or absolute ischemic damage in the brain sections from the ratsin the treatment group compared to brain sections from rats in aplacebo-treated control group.

Other methods which could alternatively be utilized to demonstrate thebenefit of the invention to reduce ischemic brain damage include thosedescribed by Nakayama, et al. in Neurology 1988,38:1667-1673; Memezawa,et al. in Stroke 1992,23:552-559; Folbergrova, et al. in Proc. Natl.Acad. Sci 1995,92:5057-5059; and Gotti, et al. in Brain Res.1990,522:290-307.

The benefit of the compounds, compositions and methods of this inventionto reduce ischemic liver damage can be demonstrated, for example, inmammals using the method of Yokoyama, et al. (Am. J. Physiol.1990;258:G564-G570). According to the procedure of Yokoyama, et al.,fasted adult male Sprague Dawley rats are anesthetized with sodiumpentobarbital (40 mg/kg i.p.), then the animals are tracheotomized andmechanically ventilated with room air. The liver is extirpated andplaced in an environmental chamber maintained at constant temperature(37° C.), then perfused through the portal vein at a constant pressureof 15 cm H₂O with a modified, hemoglobin-free Krebs-Henseleit buffer (inmM: 118 NaCl, 4.7 KCl, 27 NaHCO₃, 2.5 CaCl₂, 1.2 MgSO₄, 1.2 KH₂PO₄, 0.05EDTA, and 11 mM glucose, plus 300 U heparin). The pH of the perfusate ismaintained at 7.4 by gassing the buffer with 95% O₂—5% CO₂. Each liveris perfused at a flow rate of 20 ml/min in a single-pass manner for a 30min washout and equilibration period (preischemic period), followed by a2 hour period of global ischemia, and then a 2 hour period ofreperfusion under conditions identical to the preischemic period.Aliquots (20 ml) of the perfusate are collected during the preischemicperiod, immediately after the occlusive ischemic period, and every 30min of the 2 hour reperfusion period. The perfusate samples are assayedfor the appearance of hepatocellular enzymes, for example, aspartateamino-transferase (AST), alanine amino4transferase (ALT), and lactatedehydrogenase (LDH), which are taken to quantitatively reflect thedegree of ischemic liver tissue damage during the procedure. AST, ALT,and LDH activities in the perfusate can be determined by severalmethods, for example, by the reflectometry method using an automaticKodak Ektachem 500 analyzer reported by Nakano, et al. (Hepatology1995;22:539-545). The effect of the compounds, compositions and methodsof this invention in reducing ischemic liver damage induced by occlusionis noted based on a reduction in the release of hepatocellular enzymesimmediately following the occlusive period and/or during thepostischemic-reperfusion period in the perfused livers from the rats inthe treatment group compared to perfused livers from rats in aplacebo-treated control group.

Other methods and parameters which could alternatively be utilized todemonstrate the benefit of the compositions and methods of thisinvention in reducing ischemic liver damage include those described byNakano, et al. (Hepatology 1995;22:539-545).

Aldose Reductase Inhibitor Assays

Male Sprague-Dawley rats are rendered diabetic by injection ofstreptozocin at 55 mg/kg, i.v., in pH 4.5 citrate buffer. They are fedad libitum in controlled conditions of housing, temperature andlighting. After five weeks of diabetes, the rats are anesthetized withan overdose of pentobarbital, and tissues are rapidly removed andanalyzed for sorbitol and fructose.

Sorbitol levels are analyzed according to the method of Donald M. Eadeset al., “Rapid Analysis of Sorbitol, Galactitol, Mannitol andMyoinositol Mixtures From Biological Sources”, Journal ofChromatography, 490, 1-8, (1989).

Fructose in rat tissues is enzymatically measured using a modificationof the method of Ameyama (Methods in Enzymology, 89:20-29, 1982), inwhich ferricyanide was replaced by resazurin, a dye that is reduced tothe highly fluorescent resorufin. The amount of resorufin fluorescenceis stoichiometric with the amount of fructose oxidized by fructosedehydrogenase. The assay contains 0.1 ml neutralized 6% perchloric acidnerve extract in a final volume of 1.5 ml. Following incubation for 60minutes at room temperature in a closed drawer, sample fluorescence isdetermined at excitation=560 nm, emission=580 nm with slits of 5 mm eachin a Perkin-Elmer model 650-40 fluorescence spectrophotometer. Fructoseconcentrations are calculated by comparison with a series of knownfructose standards.

Glycogen Phosphorylase Inhibitor Assays

The three different purified glycogen phosphorylase (GP) isoenzymes,wherein glycogen phosphorylase is in the activated “a” state (referredto as glycogen phosphorylase a, or the abbreviation GPa), and referredto here as human liver glycogen phosphorylase a (HLGPa), human muscleglycogen phosphorylase a (HMGPa), and human brain glycogen phosphorylasea (HBGPa), can be obtained by the following procedures.

Expression and Fermentation

The HLGP and HMGP cDNAs are expressed from plasmid pKK233-2 (PharmaciaBiotech. Inc., Piscataway, N.J.) in E. coli strain XL-1 Blue (StratageneCloning Systems, LaJolla, Calif.). The strain is inoculated into LBmedium (consisting of 10 g tryptone, 5 g yeast extract, 5 g NaCl, and 1ml 1N NaOH per liter) plus 100 mg/L ampicillin, 100 mg/L pyridoxine and600 mg/L MnCl₂ and grown at 37°0 C. to a cell density of OD₅₅₀=1.0. Atthis point, the cells are induced with 1 mMisopropyl-1-thio-β-D-galactoside (IPTG). Three hours after induction thecells are harvested by centrifugation and cell pellets are frozen at−70°0 C. until needed for purification.

The HBGP cDNA can be expressed by several methodologies, for example, bythe method described by Crerar, et al. (J. Biol. Chem. 270:13748-13756).The method described by Crerar, et al. (J. Biol. Chem. 270:13748-13756)for the expression of HBGP is as follows: the HBGP cDNA can be expressedfrom plasmid pTACTAC in E. Coli strain 25A6. The strain is inoculatedinto LB medium (consisting of 10 g tryptone, 5 g yeast extract, 5 gNaCl, and 1 ml 1N NaOH per liter) plus 50 mg/L ampicillin and grownovernight, then resuspended in fresh LB medium plus 50 mg/L ampicillin,and reinoculated into a 40× volume of LB/amp media containing 250 μMisopropyl-1-thio-β-D-galactoside (IPTG), 0.5 mM pyridoxine and 3 mMMgCl₂ and grown at 22° C. for 48-50 hours. The cells can then beharvested by centrifugation and cell pellets are frozen at −70° C. untilneeded for purification.

The HLGP cDNA is expressed from plasmid pBlueBac III (Invitrogen Corp.,San Diego, Calif.) which is cotransfected with BaculoGold Linear ViralDNA (Pharmingen, San Diego, Calif.) into Sf9 cells. Recombinant virus issubsequently plaque-purified. For production of protein, Sf9 cells grownin serum-free medium are infected at a multiplicity of infection (moi)of 0.5 and at a cell density of 2×10⁶ cells/ml. After growth for 72hours at 27° C., cells are centrifuged, and the cell pellets frozen at−70° C. until needed for purification. Purification of GlycogenPhosphhorylase expressed in E. coli.

The E. coli cells in pellets described above are resuspended in 25 mMβ-glycerophosphate (pH 7.0) with 0.2 mM DTT, 1 mM MgCl₂, plus thefollowing protease inhibitors:

0.7 μg/mL Pepstatin A 0.5 μg/mL Leupeptin 0.2 mM phenylmethylsulfonylfluoride (PMSF), and 0.5 mM EDTA,

lysed by pretreatment with 200 μg/mL lysozyme and 3 μg/mL DNAasefollowed by sonication in 250 mL batches for 5×1.5 minutes on ice usinga Branson Model 450 ultrasonic cell disrupter (Branson Sonic Power Co.,Danbury Conn.). The E. coli cell lysates are then cleared bycentrifugation at 35,000×g for one hour followed by filtration through0.45 micron filters. GP in the soluble fraction of the lysates(estimated to be less than 1% of the total protein) is purified bymonitoring the enzyme activity (as described in GPa Activity Assaysection, below) from a series of chromatographic steps detailed below.

Immobilized Metal Affinity Chromatography (IMAC)

This step is based on the method of Luong et al (Luong et al. Joumal ofChromatography (1992) 584, 77-84.). 500 mL of the filtered solublefraction of cell lysates (prepared from approximately 160-250 g oforiginal cell pellet) are loaded onto a 130 mL column of IMACChelating-Sepharose (Pharmacia LKB Biotechnology, Piscataway, N.J.)which has been charged with 50 mM CuCl₂ and 25 mM β-glycerophosphate,250 mM NaCl and 1 mM imidazole at pH 7 equilibration buffer. The columnis washed with equilibration buffer until the A₂₈₀ returns to baseline.The sample is then eluted from the column with the same buffercontaining 100 mM imidazole to remove the bound GP and other boundproteins. Fractions containing the GP activity are pooled (approximately600 mL), and ethylenediaminetetraacetic acid (EDTA), DL-dithiothreitol(DTT), phenylmethylsulfonyl fluoride (PMSF), leupeptin and pepstatin Aare added to obtain 0.3 mM, 0.2 mM, 0.2 mM, 0.5 μg/mL and 0.7 μg/mLconcentrations respectively. The pooled GP is desalted over a SephadexG-25 column (Sigma Chemical Co., St. Louis, Mo.) equilibrated with 25 mMTris-HCl (pH 7.3), 3 mM DTT buffer (Buffer A) to remove imidazole and isstored on ice until the second chromatographic step.

5′-AMP-Sepharose Chromatography

The desalted pooled GP sample (approximately 600 mL) is next mixed with70 mL of 5′-AMP Sepharose (Pharmacia LKB Biotechnology, Piscataway,N.J.) which has been equilibrated with Buffer A (see above). The mixtureis gently agitated for one hour at 22° C. then packed into a column andwashed with Buffer A until the A₂₈₀ returns to baseline. GP and otherproteins are eluted from the column with 25 mM Tris-HCl, 0.2 mM DTT and10 mM adenosine 5′-monophosphate (AMP) at pH 7.3 (Buffer B).GP-containing fractions are pooled following identification bydetermining enzyme activity (described below) and visualizing the M_(r)approximately 97 kdal GP protein band by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) followed by silverstaining (2D-silver Stain II “Daiichi Kit”, Daiichi Pure Chemicals Co.,LTD., Tokyo, Japan) and then pooled. The pooled GP is dialyzed into 25mM β-glycerophosphate, 0.2 mM DTT, 0.3 mM EDTA, 200 mM NaCl, pH 7.0buffer (Buffer C) and stored on ice until use.

Prior to use of the GP enzyme, the enzyme is converted from the inactiveform as expressed in E. coli strain XL-1 Blue (designated GPb) (StrageneCloning Systems, La Jolla, Calif.), to the active form (designated GPa)by the procedure described in Section (A) Activation of GP below.

Purification of Glycogen Phosphorylase Expressed in Sf9 Cells

The Sf9 cells in pellets described above are resuspended in 25 mMβ-glycerophosphate (pH 7.0) with 0.2 mM DTT, 1 mM MgCl₂, plus thefollowing protease inhibitors:

0.7 μg/mL Pepstatin A 0.5 μg/mL Leupeptin 0.2 mM phenylmethylsulfonylfluoride (PMSF), and 0.5 mM EDTA,

lysed by pretreatment with 3 μg/mL DNAase followed by sonication inbatches for 3×1 minutes on ice using a Branson Model 450 ultrasonic celldisrupter (Branson Sonic Power Co., Danbury Conn.). The Sf9 cell lysatesare then cleared by centrifugation at 35,000×g for one hour followed byfiltration through 0.45 micron filters. GP in the soluble fraction ofthe lysates (estimated to be 1.5% of the total protein) is purified bymonitoring the enzyme activity (as described in GPa Activity Assaysection, below) from a series of chromatographic steps detailed below.

Immobilized Metal Affinity Chromatography (IMAC)

Immobilized Metal Affinity Chromatography is performed as described inthe section above. The pooled, desalted GP is then stored on ice untilfurther processed.

Activation of GP

Before further chromatography, the fraction of inactive enzyme asexpressed in Sf9 cells (designated GPb) is converted to the active form(designated GPa) by the following procedure described in Section (A)Activation of GP below.

Anion Exchange Chromatography

Following activation of the IMAC purified GPb to GPa by reaction withthe immobilized phosphorylase kinase, the pooled GPa fractions aredialyzed against 25 mM Tris-HCl, pH 7.5, containing 0.5 mM DTT, 0.2 mMEDTA, 1.0 mM phenylmethylsulfonyl fluoride (PMSF), 1.0 μg/mL leupeptinand 1.0 μg/mL pepstatin A. The sample is then loaded onto a MonoQ AnionExchange Chromatography column (Pharmacia Biotech. Inc., Piscataway,N.J.). The column is washed with equilibration buffer until the A₂₈₀returns to baseline. The sample is then eluted from the column with alinear gradient of 0-0.25 M NaCl to remove the bound GP and other boundproteins. GP-containing fractions elute between 0.1-0.2 M NaCl range, asdetected by monitoring the eluant for peak protein absorbance at A₂₈₀.The GP protein is then identified by visualizing the M_(r) approximately97 kdal GP protein band by sodium dodecyl sulfate polyacrylamide gelelectrophoresis (SDS-PAGE) followed by silver staining (2D-silver StainII “Daiichi Kit”, Daiichi Pure Chemicals Co., LTD., Tokyo, Japan) andthen pooled. The pooled GP is dialyzed into 25 mMN,N-bis[2-Hydroxyethyl]-2-aminoethanesulfonic acid, 1.0 mM DTT, 0.5 mMEDTA, 5 mM NaCl, pH 6.8 buffer and stored on ice until use.

Determination of GP Enzyme Activity

A) Activation of GP: Conversion of GPb to GPa

Prior to the determination of GP enzyme activity, the enzyme isconverted from the inactive form as expressed in E. coli strain XL-1Blue (designated GPb) (Stragene Cloning Systems, La Jolla, Calif.), tothe active form (designated GPa) by phosphorylation of GP usingphosphorylase kinase as follows. The fraction of inactive enzyme asexpressed in Sf9 cells (designated GPb) is also converted to the activeform (designated GPa) by the following procedure.

GP Reaction with Immobilized Phosphorylase Kinase

Phosphorylase kinase (Sigma Chemical Company, St. Louis, Mo.) isimmobilized on Affi-Gel 10 (BioRad Corp., Melvile, N.Y.) as per themanufacturer's instructions. In brief, the phosphorylase kinase enzyme(10 mg) is incubated with washed Affi-Gel beads (1 mL) in 2.5 mL of 100mM HEPES and 80 mM CaCl₂ at pH 7.4 for 4 hours at 4° C. The Affi-Gelbeads are then washed once with the same buffer prior to blocking with50 mM HEPES and 1 M glycine methyl ester at pH 8.0 for one hour at roomtemperature. Blocking buffer is removed and replaced with 50 mM HEPES(pH 7.4), 1 mM β-mercaptoethanol and 0.2% NaN₃ for storage. Prior to useto convert GPb to GPa, the Affi-Gel immobilized phosphorylase kinasebeads are equilibrated by washing in the buffer used to perform thekinase reaction, consisting of 25 mM β-glycerophosphate, 0.3 mM DTT, and0.3 mM EDTA at pH 7.8 (kinase assay buffer).

The partially purified, inactive GPb obtained from 5′-AMP-Sepharosechromatography above (from E. coli) or the mixture of GPa and GPbobtained from IMAC above (from Sf9 cells) is diluted 1:10 with thekinase assay buffer then mixed with the aforementioned phosphorylasekinase enzyme immobilized on the Affi-Gel beads. NaATP is added to 5 mMand MgCl₂ to 6 mM. The resulting mixture is mixed gently at 25° C. for30 to 60 minutes. The sample is removed from the beads and the percentactivation of GPb by conversion to GPa is estimated by determining GPenzyme activity in the presence and absence of 3.3 mM AMP. Thepercentage of total GP enzyme activity due to GPa enzyme activity(AMP-independent) is then calculated as follows:${\% \quad {of}\quad {total}\quad {HLGPa}} = \frac{{{HLGP}\quad {activity}} - {AMP}}{{{HLGP}\quad {activity}} + {AMP}}$

Alternately, the conversion of GPb to GPa can be monitored byisoelectric focusing, based on the shift in electrophoretic mobilitythat is noted following conversion of GPb to GPa. GP samples areanalyzed by isoelectric focusing (IEF) utilizing the Pharmacia PfastGelSystem (Pharmacia Biotech. Inc., Piscataway, N.J.) using precast gels(pl range 4-6.5) and the manufacturer's recommended method. The resolvedGPa and GPb bands are then visualized on the gels by silver staining(2D-silver Stain II “Daiichi Kit”, Daiichi Pure Chemicals Co., LTD.,Tokyo, Japan). Identification of GPa and GPb is made by comparison to E.coli derived GPa and GPb standards that are run in parallel on the samegels as the experimental samples.

B) GPa Activity Assay

The disease/condition treating/preventing activities described herein ofthe glycogen phosphorylase inhibitor compounds of this invention can beindirectly determined by assessing the effect of the compounds of thisinvention on the activity of the activated form of glycogenphosphorylase (GPa) by one of two methods; glycogen phosphorylase aactivity is measured in the forward direction by monitoring theproduction of glucose-1-phosphate from glycogen or by following thereverse reaction, measuring glycogen synthesis from glucose-1-phosphateby the release of inorganic phosphate. All reactions can be run intriplicate in 96-well microtiter plates and the change in absorbance dueto formation of the reaction product is measured at the wavelengthspecified below in a MCC/340 MKII Elisa Reader (Lab Systems, Finland),connected to a Titertech Microplate Stacker (ICN Biomedical Co,Huntsville, Ala.).

To measure the GPa enzyme activity in the forward direction, theproduction of glucose-1-phosphate from glycogen is monitored by themultienzyme coupled general method of Pesce et al. [Pesce, M. A.,Bodourian, S. H., Harris, R. C. and Nicholson, J. F. (1977) ClinicalChemistry 23, 1711-1717] modified as follows: 1 to 100 μg GPa, 10 unitsphosphoglucomutase and 15 units glucose-6-phosphate dehydrogenase(Boehringer Mannheim Biochemicals, Indianapolis, Ind.) are diluted to 1mL in Buffer A (described hereinafter). Buffer A is at pH 7.2 andcontains 50 mM HEPES, 100 mM KCl, 2.5 mM ethyleneglycoltetraacetic acid(EGTA), 2.5 mM MgCl₂, 3.5 mM KH₂PO₄ and 0.5 mM dithiothreitol. 20 μl ofthis stock is added to 80 μl of Buffer A containing 0.47 mg/mL glycogen,9.4 mM glucose, 0.63 mM of the oxidized form of nicotinamide adeninedinucleotide phosphate (NADP+). The compounds to be tested are added as5 μL of solution in 14% dimethylsulfoxide (DMSO). prior to the additionof the enzymes. The basal rate of GPa enzyme activity in the absence ofinhibitors is determined by adding 5 μL of 14% DMSO and afully-inhibited rate of GPa enzyme activity is obtained by adding 20 μLof 50 mM of the positive control test substance, caffeine. The reactionis followed at room temperature by measuring the conversion of oxidizedNADP+ to reduced NADPH at 340 nm.

To measure the GPa enzyme activity in the reverse direction, theconversion of glucose-1-phosphate into glycogen plus inorganic phosphateis measured by the general method described by Engers et al. [Engers, H.D., Shechosky, S. and Madsen, N. B. (1970) Can. J. Biochem. 48, 746-754]modified as follows: 1 to 100 μg GPa is diluted to 1 mL in Buffer B(described hereinafter). Buffer B is at pH 7.2 and contains 50 mM HEPES,100 mM KCl, 2.5 mM EGTA, 2.5 mM MgCl₂ and 0.5 mM dithiothreitol. 20 μLof this stock is added to 80 μL of Buffer B with 1.25 mg/mL glycogen,9.4 mM glucose, and 0.63 mM glucose-1-phosphate. The compounds to betested are added as 5 μL of solution in 14% DMSO prior to the additionof the enzyme. The basal rate of GPa enzyme activity in the absence ofadded inhibitors is determined by adding 5 μL of 14% DMSO and afully-inhibited rate of GPa enzyme activity is obtained by adding 20 μLof 50 mM caffeine. This mixture is incubated at room temperature for 1hour and the inorganic phosphate released from the glucose-1-phosphateis measured by the general method of Lanzetta et al. [Lanzetta, P. A.,Alvarez, L. J., Reinach, P. S. and Candia, O. A. (1979) Anal. Biochem.100, 95-97] modified as follows: 150 μL of 10 mg/mL ammonium molybdate,0.38 mg/mL malachite green in 1 N HCl is added to 100 μL of the enzymemix. After a 20 minute incubation at room temperature, the absorbance ismeasured at 620 nm.

The above assays carried out with a range of concentrations of testcompound allows the determination of an IC₅₀ value (concentration oftest compound required for 50% inhibition) for the in vitro inhibitionof GPa enzyme activity by that test compound.

Administration of the compounds of this invention can be via any methodwhich delivers a compound of this invention preferentially to thedesired tissue (e.g., liver and/or cardiac tissues). These methodsinclude oral routes, parenteral, intraduodenal routes, etc. Generally,the compounds of the present invention are administered in single (e.g.,once daily) or multiple doses or via constant infusion.

The compounds of this invention are useful, for example, in reducing orminimizing damage effected directly to any tissue that may besusceptible to ischemia/reperfusion injury (e.g., heart, brain, lung,kidney, liver, gut, skeletal muscle, retina) as the result of anischemic event (e.g., myocardial infarction). The active compound istherefore usefully employed prophylactically to prevent, i.e.(prospectively or prophylactically) to blunt or stem, tissue damage(e.g., myocardial tissue) in patients who are at risk for ischemia(e.g., myocardial ischemia).

Generally, the compounds of this invention are administered orally, orparenterally (e.g., intravenous, intramuscular, subcutaneous orintramedullary). Topical administration may also be indicated, forexample, where the patient is suffering from gastrointestinal disordersor whenever the medication is best applied to the surface of a tissue ororgan as determined by the attending physician.

The amount and timing of compounds administered will, of course, bedependent on the subject being treated, on the severity of theaffliction, on the manner of administration and on the judgement of theprescribing physician. Thus, because of patient to patient variability,the dosages given below are a guideline and the physician may titratedoses of the drug to achieve the treatment that the physician considersappropriate for the patient. In considering the degree of treatmentdesired, the physician must balance a variety of factors such as age ofthe patient, presence of preexisting disease, as well as presence ofother diseases (e.g., cardiovascular disease).

Thus, for example, in one mode of administration the compounds of thisinvention may be administered just prior to surgery (e.g., withintwenty-four hours before surgery for example cardiac surgery) during orsubsequent to surgery (e.g., within twenty-four hours after surgery)where there is risk of myocardial ischemia. The compounds of thisinvention may also be administered in a chronic daily mode.

An amount of the compounds of this invention is used that is effectivefor ischemic protection. A preferred dosage is about 0.001 to 100mg/kg/day of the compound of this invention. An especially preferreddosage is about 0.01 to 50 mg/kg/day of the compound of this invention.

The compounds of the present invention are generally administered in theform of a pharmaceutical composition comprising at least one of thecompounds of this invention together with a pharmaceutically acceptablevehicle or diluent. Thus, the compounds of this invention can beadministered individually or together in any conventional oral,parenteral, rectal or transdermal dosage form.

For oral administration a pharmaceutical composition can take the formof solutions, suspensions, tablets, pills, capsules, powders, and thelike. Tablets containing various excipients such as sodium citrate,calcium carbonate and calcium phosphate are employed along with variousdisintegrants such as starch and preferably potato or tapioca starch andcertain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type are also employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. When aqueous suspensions and/or elixirs are desired for oraladministration, the compounds of this invention can be combined withvarious sweetening agents, flavoring agents, coloring agents,emulsifying agents and/or suspending agents, as well as such diluents aswater, ethanol, propylene glycol, glycerin and various like combinationsthereof.

For purposes of parenteral administration, solutions, for example, insesame or peanut oil or in aqueous propylene glycol can be employed, aswell as sterile aqueous solutions of the corresponding water-solublesalts. Such aqueous solutions may be suitably buffered, if necessary,and the liquid diluent first rendered isotonic with sufficient saline orglucose. These aqueous solutions are especially suitable forintravenous, intramuscular, subcutaneous and intraperitoneal injectionpurposes. In this connection, the sterile aqueous media employed are allreadily obtainable by standard techniques well-known to those skilled inthe art.

For purposes of transdermal (e.g.,topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, are prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. For examples of methodsof preparing pharmaceutical compositions, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

Pharmaceutical compositions according to the invention may contain forexample 0.0001%-95% of the compound(s) of this invention. In any event,the composition or formulation to be administered will contain aquantity of a compound(s) according to the invention in an amounteffective to treat the disease/condition of the subject being treated.

The two different compounds of this combination of this invention can beco-administered simultaneously or sequentially in any order, or as asingle pharmaceutical composition comprising a compound of Formula I andan aldose reductase inhibitor as described above or a glycogenphosphorylase inhibitor as described above or a cardiovascular agent.

Since the present invention has an aspect that relates to the treatmentof the disease/conditions described herein with a combination of activeingredients which may be administered separately, the invention alsorelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof Formula I a prodrug thereof or a salt of such compound or prodrug anda second compound as described above. The kit comprises means forcontaining the separate compositions such as a container, a dividedbottle or a divided foil packet. Typically the kit comprises directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral and parenteral), areadministered at different dosage intervals, or when titration of theindividual components of the combination is desired by the prescribingphysician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of Formula I compound canconsist of one tablet or capsule while a daily dose of the secondcompound can consist of several tablets or capsules and vice versa. Thememory aid should reflect this.

In another specific embodiment of the invention, a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

The compounds of this invention generally will be administered in aconvenient formulation. The following formulation examples areillustrative only and are not intended to limit the scope of the presentinvention.

In the formulations which follow, “active ingredient” means acompound(s) of this invention.

Formulation 1 Gelatin Capsules Hard gelatin capsules are prepared usingthe following: Ingredient Quantity (mg/capsule) Active ingredient0.25-100  Starch, NF  0-650 Starch flowable powder  0-50 Silicone fluid350 centistokes  0-15

A tablet formulation is prepared using the ingredients below:

Formulation 2 Tablets Ingredient Quantity (mg/tablet) Active ingredient0.25-100  Celluose, microcrystalline 200-650 Silicon dioxide, fumed 10-650 Stearate acid  5-15

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 0.25-100 mg of active ingredientsare made up as follows:

Formulation 3 Tablets Ingredient Quantity (mg/tablet) Active ingredient0.25-100 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone(as 10% solution in water) 4 Sodium carboxymethyl cellulose 4.5Magnesium stearate 0.5 Talc 1

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Suspensions each containing 0.25-100 mg of active ingredient per 5 mldose are made as follows:

Formulation 4 Suspensions Ingredient Quantity (mg/5 ml) Activeingredient 0.25-100 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v. Purified Waterto 5 mL

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form smoothpaste. The benzoic acid solution, flavor, and color are diluted withsome of the water and added, with stirring. Sufficient water is thenadded to produce the required volume. An aerosol solution is preparedcontaining the following ingredients:

Formulation 5 Aerosol Ingredient Quantity (% by weight) Activeingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane)74.00

The active ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C., and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remaining propellant. The valve units arethen fitted to the container.

Suppositories are prepared as follows:

Formulation 6 Suppositories Ingredient Quantity (mg/suppository) Activeingredient 250 Saturated fatty acid glycerides 2,000

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimal necessary heat. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

An intravenous formulation is prepared as follows:

Formulation 7 Intravenous Solution Ingredient Quantity Active ingredient25 mg-10,000 mg Isotonic saline 1,000 mL

The solution of the above ingredients is intravenously administered to apatient.

The active ingredient above may also be a combination of agents.

General Experimental Procedures

NMR spectra were recorded on a Varian XL-300 (Varian Co., Palo Alto,Calif.) a Bruker AM-300 spectrometer (Bruker Co., Billerica, Mass.) or aVarian Unity 400 at about 23° C. at 300 or 400 MHz for proton. Chemicalshifts are expressed in parts per million downfield fromtrimethylsilane. The peak shapes are denoted: as follows: s, singlet; d,doublet; t, triplet, q, quartet; m, multiplet; bs,=broad singlet.Resonances designated as exchangeable did not appear in a separate NMRexperiment where the sample was shaken with several drops of D₂O in thesame solvent. Atmospheric pressure chemical ionization mass spectra(APCIMS) were obtained on a Fisons Platform II Spectrometer. Chemicalionization mass spectra (CIMS) were obtained on a Hewlett-Packard 5989instrument (Hewlett-Packard Co., Palo Alto, Calif.) (ammonia ionization,PBMS). Where the intensity of chlorine or bromine-containing ions aredescribed the expected intensity ratio was observed (approximately 3:1for ³⁵Cl/³⁷Cl-containing ions and 1:1 for ⁷⁹Br/⁸¹Br-containing ions) andM is based on ³⁵Cl and ⁷⁹Br. In some cases only representative ¹H NMRand APCIMS peaks are given.

Column chromatography was performed with either Baker Silica Gel (40 μm)(J. T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (EM Sciences,Gibbstown, N.J.) in glass columns or in Flash 40™ or Flash 12™ (Biotage)(Charlottesville, Va.) columns under low nitrogen pressure. RadialChromatography was performed using a Chromatron, (Harrison Research)(Palo Alto, Calif.) Unless otherwise specified, reagents were used asobtained from commercial sources. Dimethylformamide, 2-propanol,tetrahydrofuran, and dichloromethane used as reaction solvents were theanhydrous grade supplied by Aldrich Chemical Company (Milwaukee, Wis.).Microanalyses were performed by Schwarzkopf Microanalytical Laboratory,Woodside, N.Y. The terms “concentrated” and “coevaporated” refer toremoval of solvent at water aspirator pressure on a rotary evaporatorwith a bath temperature of less than 50° C. Reactions conducted at“0-20° C.” or “0-25° C.” were conducted with initial cooling of thevessel in an insulated ice bath which was allowed to warm to roomtemperature over several hours. The abbreviation “min” and “h” stand for“minutes” and “hours” respectively.

Reference to the hydrochloride salt in the Example names below includesmono- or di-salts as appropriate in the particular Example.

EXAMPLE 1 Ethyl 5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylate

Titanium tetrachloride (0.28 mL, 2.56 mmol) was added to a solution ofethyl diazoacetoacetate (0.35 mL, 2.56 mmol) and aniline (0.47 mL, 5.12mmol) in 5 mL of dichloroethane. After heating at reflux for 16 hours,the solution was quenched with an aqueous 2 N KOH solution, and 10 mLeach of hexanes and diethyl ether were added. The separated organicphase was washed with water, dried over sodium sulfate, filtered andconcentrated in vacuo. The product was purified by silica gelchromatography eluting with 0-15% ethyl acetate in hexanes to provide168 mg of the title compound.

¹H NMR (CD₃OD) δ1.4 (t, 3H), 2.6 (s, 3H), 4.4 (q, 2H), 7.5-7.6 (m, 2H),7.6-7.7 (m, 3H).

EXAMPLE 2 Methyl 4-methyl-5-phenyl-4H-1,2,4-triazole-3-carboxylate

N-Methyl benzamide (5 g, 37 mmol) was converted to the thioamide bytreatment with Lawesson's reagent (10 g, 25 mmol) in dimethoxyethane(100 mL) at 60° C. for 4 hours. After an aqueous extractive work-up withmethylene chloride, drying over sodium sulfate, and filtering, theorganic phases were concentrated in vacuo to afford 2.68 g of thethioamide as a yellow solid. This material (2.86 g, 17.75 mmol) wastreated directly with methyl iodide (3.87 mL, 62 mmol) in acetone (100mL). After stirring overnight at room temperature, the mixture wasconcentrated in vacuo to afford 2.48 g of theN,S-dimethylisothiobenzamide hydroiodide as a yellow solid. Thismaterial (2.48 g, 8.46 mmol) was dissolved in 50 mL of methanol andcooled in an ice bath as anhydrous hydrazine (0.518 mL, 16.51 mmol,dissolved in 10 mL of methanol) was slowly added to the solution. Whilecooling in an ice water bath, the mixture was stirred for 2.5 h andether (about 200 mL) was added to form a precipitate. The resultingslurry was stirred for 3 additional hours before the solid was collectedby filtration and rinsed with ether, to afford 2.15 g of the N-methylbenzamidrazone hydroiodide as a white solid.

¹H NMR (CD₃OD) δ2.95 (s, 3H), 7.6 (m, 4H), 7.7 (m, 1H).

The preceding N-methyl benzamidrazone hydroiodide (1 g, 3.61 mmol) wasdissolved in 5 mL of pyridine and treated with methyl oxalyl chloride(0.89 mL, 9.6 mmol). After the exothermic addition, the reaction mixturewas stirred at room temperature overnight before being concentrated invacuo. The resulting residue was combined with 10 mL of water andextracted with ethyl acetate (3×75 mL). The combined organic phases werewashed with water (2×25 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo to give a yellow solid which was purified bysilica gel chromatography eluting with 5% methanol in methylene chlorideto afford 200 mg of the title compound.

¹H NMR (CD₃OD) δ3.9 (s, 3H), 4.0 (s, 3H), 7.6 (m, 3H), 7.7 (m, 2H).

The title compounds of Examples 3A-3T were prepared using proceduresanalogous to that described in Klinsberg, E. Synthesis 1972, 475.

EXAMPLE 3A 5-Methyl-2-(4-methoxyphenyl)-2H-1,2,3-triazole-4-carboxylicacid

Acetoacetanilide (25.0 g, 0.14 mol) and sodium nitrite (12.65 g, 0.18mol) were dissolved in aqueous sodium hydroxide solution (140 ml, 1 N)and the resulting solution was added dropwise over 20 min to an aqueoussolution of sulfuric acid (120 ml conc. H₂SO₄ in 950 ml water) cooled inan ice bath. The reaction mixture was stirred at 0° C. for 30 min, thenthe precipitate was filtered and washed with water to yield2-hydroxyiminoacetanilide (22.64 g, 78% yield) as a pale yellow solid.

Sodium methoxide (0.89 g, 0.017 mol) was added to a solution of4-methoxyphenylhydrazine hydrochloride (2.89 g, 0.016 mol) in 10 mlethanol and after 5 min the mixture was filtered and the filtrate addedto a warm solution of 2-hydroxyiminoacetoacetanilide (3.25 g, 0.0158mol) in 5 ml ethanol. The resulting solution was briefly heated toreflux, then allowed to cool to room temperature, whereupon aprecipitate formed. The precipitate was filtered and washed with 2:1hexane/ethyl acetate to yield2-hydroxyimino-3-(4-methoxyphenyl)hydrazonobutanoic acid anilide as ayellow solid (3.16 g, 61% yield).

2-Hydroxyimino-3-(4-methoxyphenyl)hydrazonobutanoic acid anilide (3.16g, 0.01 mol) was added over a 2 min period to a refluxing solution ofpotassium hydroxide (3.2 g, 0.05 mol) in 12 ml 2-ethoxyethanol. Thereaction mixture was refluxed for 15 min, then cooled to roomtemperature. The precipitate that formed was filtered and washed withdiethyl ether. The solid was dissolved in 15 ml water and the resultingsolution was acidified with dilute aqueous hydrochloric acid. Theaqueous solution was extracted with 3×20 ml ethyl acetate and thecombined ethyl acetate extracts were washed with 40 ml water and 40 mlbrine, dried (anhydrous sodium sulfate) and concentrated in vacuo toyield the title compound (0.84 g) as a reddish solid. By a similartreatment of the solids that formed in the filtrate from the ether wash,a further 0.805 g of the product was obtained (1.65 g total yield, 73%yield).

¹H NMR (CD₃OD) δ2.58 (s, 3H); 3.83 (s, 3H); 6.9-7.0 (m, 2H); 7.74 (d,1H); 7.99 (d, 1H).

The title compounds of Examples 3B-3T were prepared using proceduresanalogous to that used for Example 3A.

EXAMPLE 3B 5-Methyl-2-(4-sulfamoylphenyl)-2H-1,2,3-triazole-4-carboxylicacid

21% yield.

¹H NMR (CD₃OD) δ2.59 (s, 3H); 8.05 (d, 2H); 8.25 (d, 2H).

EXAMPLE 3C 5-Methyl-2-(2-methoxyphenyl)-2H-1,2,3-triazole-4-carboxylicacid

98% yield.

¹H NMR (CDCl₃) δ2.33 (s, 3H); 3.87 (s, 3H); 6.97-7.14 (m, 2H); 7.3-7.55(m, 2H).

EXAMPLE 3D5-Methyl-2-(4-methylsulfonylphenyl)-2H-1,2,3-triazole-4-carboxylic acid

50% yield.

¹H NMR (CDCl₃) δ2.6 (s, 3H); 3.06 (s, 3H); 8.01 (d, 2H); 8.29 (d, 2H).

EXAMPLE 3E 5-Methyl-2-(3-methoxyphenyl)-2H-1,2,3-triazole-4-carboxylicacid

46% yield.

¹H NMR (CDCl₃) δ2.34 (s, 3H); 3.82 (s, 3H); 6.92 (m, 1H); 7.36 (t, 1H);7.61-7.68 (m, 2H).

EXAMPLE 3F 5-Methyl-2-(5-quinolinyl)-2H-1,2,3-triazole-4-carboxylic acid

67% yield.

¹H NMR (DMSO-d₆) δ2.56 (s, 3H); 7.67 (m, 1H); 7.89-7.99 (m, 2H); 8.2 (d,1H); 8.55 (d, 1H); (9.01, s, 1H).

EXAMPLE 3G 5-Methyl-2-(5-isoquinolinyl)-2H-1,2,3-triazole-4-carboxylicacid

31 % yield.

¹H NMR (DMSO-d₆) δ2.57 (s, 3H); 7.85 (t, 1H); 8.09 (d, 1H); 8.17 (d,1H); 8.34 (d, 1H), 8.63 (d, 1H); 9.48 (s, 1H).

EXAMPLE 3H 5-Methyl-2-(p-tolyl)-2H-1,2,3 triazole-4-carboxylic acid

44% yield

¹H NMR (400 MHz, CDCl₃) δ2.35 (s, 3H), 2.50 (s, 3H), 7.36 (d, J=8, 2H),7.87 (d, J=8, 2H), 13.42 (s, 1H).

APCIMS 216 [M−1]⁻

EXAMPLE 3I 2-(4-Chlorophenyl)-5-methyl-2H-1,2,3-triazole-4-carboxylicacid

22% yield

¹H NMR (400 MHz, CDCl₃) δ2.5 (s, 3H), 7.41 (d, J=8, 2H), 8.00 (d, J=8,2H), 13.53 (s, 1H).

APCIMS 236 [M−1]⁻

EXAMPLE 3J2-(3,4-Dichlorophenyl)-5-methyl-2H-1,2,3-triazole-4-carboxylic acid

14% yield

¹H NMR (400 MHz, CDCl₃) δ2.48 (s, 3H), 7.43 (d, J=8, 1H), 7.86 (dd,J=2.4, 8.8, 1H), 8.15 (d, J=2.4, 1H).

APCIMS 271 [M−1]⁻

EXAMPLE 3K 2.5-Diphenyl-2H-1,2,3-triazole-4-carboxylic acid

29% yield

¹H NMR (400 MHz, DMSO) δ7.48 (m, 4H) 7.60 (m, 2H), 7.88 (m, 2H), 8.10(m, 2H), 13.61 (s, 1H).

APCIMS 264 [M−1]⁻

EXAMPLE 3L2-(3,5-Dichlorophenyl)-5-methyl-2H-1,2,3-triazole-4-carboxylic acid

40% yield

¹H NMR (400 MHz, DMSO) δ2.47 (s, 3H), 7.67 (d, J=1.6, 1H), 7.92 (d,J=1.6, 2H).

APCIMS 270 [M−1]⁻

EXAMPLE 3M 5-Methyl-2-(m-tolyl)-2H-1,2,3-triazole-4-carboxylic acid

66% yield

¹H NMR (400 MHz, DMSO) δ2.37 (s, 3H), 2.47 (s, 3H), 7.23 (m, 1H), 7.41(m, 1H), 7.77 (m, 2H), 13.40 (bs, 1H).

APCIMS 216 [M−1]⁻

EXAMPLE 3N 2-(3-Chlorophenyl)-5-methyl-2H-1,2,3-triazole-4-carboxylicacid

62% yield

¹H NMR (400 MHz, DMSO) δ2.50 (s, 3H), 7.51 (m, 1H), 7.59 (m, 1H), 7.96(m, 2H).

APCIMS 236 [M−1]⁻

EXAMPLE 3O 2-Phenyl-5-(n-propyl)-2H-1,2,3-triazole-4-carboxylic acid

20% yield.

¹H NMR (400 MHz, CD₃OD) δ1.00 (t, J=7, 3H), 1.78 (m, 2H), 3.13 (m, 2H),7.42 (m, 1H), 7.52 (m, 2H), 8.07 (m, 2H).

APCIMS 230 [M−1]⁻

EXAMPLE 3P 2-Phenyl-5-ethyl-2H-1,2,3-triazole-4-carboxylic acid

63% yield

¹H NMR (400 MHz, CD₃OD) δ1.33 (t, J=7.6, 3H), 3.15 (m, 2H), 7.41 (m,1H), 7.52 (m, 2H), 8.08 (m, 2H).

APCIMS 216 [M−1]⁻

EXAMPLE 3Q5-Methyl-2-(3-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxylic acid

37% yield

¹H NMR (400 MHz, CD₃OD) δ2.57 (s, 3H), 7.71 (m, 2H), 8.32 (m, 2H).

APCIMS 270 [M−1]⁻

EXAMPLE 3R 2-(1-Naphthalenyl)-5-methyl-2H-1,2,3-triazole-4-carboxylicacid

54% yield

¹H NMR (400 MHz, DMSO-d₆) δ2.57 (s, 3H), 7.64 (m, 3H), 7.82 (d, J=7.2,1H), 7.94 (dd, J=2, 5.6, 1H), 8.12 (m, 2H).

APCIMS 252 [M−1]⁻

EXAMPLE 3S 5-Methyl-2-(8-quinolinyl)-2H-1,2,3-triazole-4-carboxylic acid

24% yield

¹H NMR (400 MHz, CD₃OD) δ2.63 (s, 3H), 7.64 (dd, J=4.4, 8, 1H), 7.76 (t,J=7.8, 1H), 8.00 (dd, J=1.4, 7.4, 1H), 8.18 (dd, J=1.2, 8.4, 1H), 8.50(dd, J=1.6, 8.4, 1H), 8.88 (dd, J=1.6, 4, 1H).

APCIMS 253 [M−1]⁻

EXAMPLE 3T 2-(3-Bromophenyl)-5-methyl-2H-1,2,3-triazole-4-carboxylicacid

44% yield

¹H NMR (400 MHz, DMSO-d₆) δ2.47 (s, 3H), 7.51 (t, J=8, 1H), 7.64 (dd,J=8.2,1, 1H), 7.98 (dt, J=8.0,1, 1H), 8.10 (d, J=1, 1H), 13.54 (bs, 1H).

APCIMS 236 [M−1]⁻

EXAMPLE 45-(N,N-Dimethylcarbamoyl)-2-phenyl-2H-1,2,3-triazole-4-carboxylic acid

A solution of 5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxylic acid(10.2 g, 50 mmol) and NaOH (17.6 g, 440 mmol) in water (375 mL) at 23°C. was treated with KMnO₄ (30.8 g, 195 mmol). The resulting solution washeated at reflux for 17 h, cooled to 23° C. and treated with ethanol (50mL). The resulting mixture was filtered to remove MnO₂. The filtrate wasacidified with HCl (conc.) to pH 1. The resulting white solid wascollected by filtration. The filtrate was concentrated to half volumeand more solid was collected by filtration. The two combined batches ofsolid were dried in vacuo to afford 11.1 g (95%) of2-phenyl-2H-1,2,3-triazole-4,5-dicarboxylic acid.

A suspension of 2-phenyl-2H-1,2,3-triazole-4,5-dicarboxylic acid (2.00g, 8.58 mmol) in methanol (50 mL) at 23° C. was treated with H₂SO₄(conc., 0.477 mL, 8.58 mmol). The mixture was refluxed for 15 h, cooledto 23° C. and partitioned between NaHCO₃ (sat. aq. sol.) and EtOAc. Theaqueous layer was extracted with another portion of EtOAc. The combinedorganic extracts were washed with brine, dried over MgSO₄ andConcentrated in vacuo to afford 1.61 g (72%) of dimethyl2-phenyl-2H-1,2,3-triazole-4,5-dicarboxylate.

¹H NMR (400 MHz, CDCl₃) δ4.01 (s, 6H), 7.49 (m, 3H), 8.13 (m, 2H).

APCIMS 262 [M+1]⁺

A solution of dimethyl 2-phenyl-2H-1,2,3-triazole-4,5-dicarboxylate(0.522 g, 2.00 mmol) in methanol (40 mL) at 23° C. was treated with asolution of KOH (0.236 g, 4.20 mmol) in methanol (5 mL). The resultingsolution was stirred at 23° C. for 17 h and partitioned between NaHCO₃(sat. aq. sol.) and ether. The aqueous layer was washed with ether andacidified carefully to pH 1 with HCl (conc.). The resulting mixture, wasextracted with EtOAc. The organic extract was washed with brine, driedover MgSO₄ and concentrated in vacuo. The residue was purified by radialchromatography (2 mm plate, CH₂Cl₂-methanol-acetic acid 90:10:1) toafford 0.42 g (85%) of5-methoxycarbonyl-2-phenyl-2H-1,2,3-triazole-4carboxylic acid.

A solution of 5-methoxycarbonyl-2-phenyl-2H-1,2,3-triazole-4-carboxylicacid (0.203 g, 0.82 mmol) in dry DMF (3 mL) at 23° C. was treated withcarbonyldiimidazole (0.146 g, 0.90 mmol). The resulting mixture wasstirred for 1.5 h at 23° C., cooled to 0° C. and treated withdimethylamine (2.0 M in THF, 2.05 mL, 4.10 mmol). The resulting mixturewas allowed to warm to 23° C. over 16 h and concentrated in vacuo. Theresidue was partitioned between water and EtOAc. The aqueous layer wasextracted with an additional portion of EtOAc. The combined organicextracts were washed with HCl (1 M), brine, NaHCO₃ (sat. aq. sol.) andbrine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by filtering it through a silica gel plug (EtOAc-hexanes 50:50)to afford 0.201 g (89%) of methyl5-(N,N-dimethylcarbamoyl)-2-phenyl-2H-1,2,3-triazole-4-carboxylate.

A solution of methyl5-(N,N-dimethylcarbamoyl)-2-phenyl-2H-1,2,3-triazole-4-carboxylate(0.195 g, 0.71 mmol) in THF (3.6 mL) at 23° C. was treated with LiOH (1M aq., 3.6 mL, 3.6 mmol). The resulting suspension was stirred for 15min at 23° C. and partitioned between ether and water. The aqueous layerwas acidified to pH 1 with HCl (conc.). The resulting white solid wascollected by filtration, washed with water, and air-dried to provide0.164 g (89%) of5-(N,N-dimethylcarbamoyl)-2-phenyl-2H-1,2,3-triazole-4-carboxylic acid.

¹H NMR (400 MHz, CDCl₃) δ3.26 (bs, 3H), 3.65 (bs, 3H), 7.50 (bs, 3H),8.13 (bs, 2H).

APCIMS 261 [M+1]⁺

EXAMPLE 5 (5-Methyl-2-phenyl-2H-1,2,3-triazole-4-carbonyl)guanidinehydrochloride

Guanidine hydrochloride (2.42 g, 25.32 mmol) was dissolved in 20 ml ofanhydrous methanol and then treated with sodium methoxide (1.50 g, 27.83mmol), added in one portion at room temperature. The reaction mixturewas stirred under nitrogen for 1 hour, then filtered under a nitrogenatmosphere. The solids were washed with anhydrous methanol (3×10 ml) andthe filtrate concentrated under reduced pressure. Anhydrous benzene (60ml) was added to the residue, the mixture reconcentrated in vacuo andthe residue was dried under high vacuum. Anhydrous dimethylformamide (10ml), anhydrous tetrahydrofuran (20 ml) and methyl4-methyl-2-phenyl-2H-1,2,3-triazole-5-carboxylate (1.00 g, 4.60 mmol)were added to the solid residue and the resulting mixture was heated at70° C. under nitrogen for 7 h, then stirred at ambient temperatureovernight. The reddish colored solution was then diluted with water (90ml) to give the free base corresponding to the title compound as a tansolid (0.53 g, 47% yield).

APCIMS 242.9 [M−H]⁻

¹H NMR (DMSO-d₆) δ2.54 (s, 3H), 7.37 (t, 1H), 7.53 (m, 2H), 7.92 (m,2H).

The title compound was prepared by suspending the free base (100 mg,0.41 mmol) in 10 ml of diethyl ether and bubbling excess hydrogenchloride gas into the mixture. The mixture was stirred under nitrogenovernight then filtered to give the title compound as a white solid(85.2 mg, 74% yield).

¹H NMR (DMSO-d₆) δ2.55 (s, 3H), 7.48 (t, 1H), 7.6 (m, 2H), 8.12 (m, 2H),8.56 (s, 2H), 8.73 (s, 2H), 11.62 (s, 1H).

EXAMPLE 6A[5-Methyl-2-(2-methoxyphenyl)-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

Guanidine hydrochloride (5.29 g, 55.3 mmol) was dissolved in 30 ml ofanhydrous methanol and then treated with sodium methoxide (3.04 g, 56.2mmol), added in one portion at room temperature. The reaction mixturewas stirred under nitrogen for 1 hour, then filtered under a nitrogenatmosphere. The solids were washed with anhydrous methanol (3×15 ml) andthe filtrate concentrated under reduced pressure. Anhydrous benzene (60ml) was added to the residue, the mixture reconcentrated in vacuo andthe resulting guanidine free base was dried under high vacuum. Theresidue was suspended in a mixture of 10 ml anhydrous THF and 10 mlanhydrous DMF and the resulting mixture was used in the subsequent step.

A solution of5-methyl-2-(2-methoxyphenyl)-2H-1,2,3-triazole-4-carboxylic acid (2.15g, 9.2 mmol) and carbonyldiimidazole (1.64 g, 10 mmol) in 30 ml DMF wasstirred at room temperature under nitrogen for 2 h. The resultingmixture was added to the mixture of guanidine in THF and DMF previouslyprepared and the reaction mixture was stirred overnight under nitrogenat room temperature. The reaction mixture was then poured into 200 ml ofcold water and the aqueous mixture was extracted with 10×70 ml ethylacetate. The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo to an orangish solid (1.83 g). The crude productwas triturated with diethyl ether to yield 0.59 g of the free basecorresponding to the title compound. The title compound was prepared bydissolving the free base in 40 ml methanol and bubbling excess hydrogenchloride gas into the solution. After stirring for several hours theresulting precipitate was filtered and washed with diethyl ether to givethe title compound as a tan solid (0.5 g, 17% yield).

¹H NMR (DMSO-d₆) δ2.54 (s, 3H); 3.8 (s, 3H); 7.14 (t, 1H); 7.32 (d, 1H);7.52-7.7 (m, 3H); 8.45 (s, 2H); 8.66 (s, 2H); 11.37 (s, 1H).

The title compounds of Examples 6B-6V were prepared according toprocedures analogous to those described in Example 6A.

EXAMPLE 6B[5-Methyl-2-(4-methoxyphenyl)-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

50% yield.

¹H NMR (DMSO-d₆) δ2.55 (s, 3H); 3.83 (s, 3H); 7.15 (d, 2H); 8.06 (d,2H); 8.56 (s, 2H); 8.73 (s, 2H); 11.58 (s, 1H).

EXAMPLE 6C [5-Methyl2-(4-sulfamoylphenyl)-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

50% yield.

¹H NMR (DMSO-d₆) δ2.58 (s, 3H); 7.55 (s, 2H); 8.04 (d, 2H); 8.35 (d,2H); 8.62 (s, 2H); 8.79 (s, 2H); 11.84 (s, 1H).

EXAMPLE 6D[5-Methyl-2-(4-methylsulfonylphenyl)-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

20% yield.

¹H NMR (DMSO-d₆) δ2.58 (s, 3H); 3.3 (s, 3H); 8.15 (d, 2H); 8.47 (d, 2H);8.81 (s, 2H); 8.99 (s, 2H); 12.12 (s, 1H).

EXAMPLE 6E[5-Methyl-2-(3-methoxyphenyl)-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

35% yield.

¹H NMR (DMSO-d₆) δ2.47 (s, 3H); 3.86 (s, 3H); 7.05 (dd, 1H); 7.5 (t,1H); 7.67 (m, 2H); 8.47(bs, 2H); 8.74 (bs, 2H).

EXAMPLE 6F[5-Methyl-2-(5-quinolinyl)-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

67% yield.

¹H NMR (DMSO-d₆) δ2.62 (s, 3H); 7.79 (m 1H); 8.02 (m, 1H); 8.17 (d, 1H);8.32 (d, 1H); 8.69 (bs, 4H); 8.92 (d, 1H); 9.12 (s, 1H); 11.7 (s, 1H).

EXAMPLE 6G[5-Methyl-2-(5-isoquinolinyl)-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

52% yield.

¹H NMR (DMSO-₆) δ2.63 (s, 3H); 8.01 (t, 1H); 8.46 (d, 1H); 8.52 (d, 1H);8.7 (m, 6H); 9.74 (s, 1H); 11.7 (s, 1H).

EXAMPLE 6H [2-(p-Tolyl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidine

97% yield

¹H NMR (400 MHz, DMSO) δ2.30 (s, 3H), 2.50 (s, 3H), 7.30 (d, J=8, 2H),7.79 (d, J=8, 2H).

APCIMS 259 [M+1]⁺

EXAMPLE 6I[2-(4-Chlorophenyl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidine

98% yield

¹H NMR (400 MHz, DMSO) δ2.51 (s, 3H), 7.56 (d, J=8, 2H), 7.91 (d, J=8,2H).

APCIMS 279 [M+1]⁺

EXAMPLE 6J[2-(3,4-Dichlorophenyl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidine

100% yield

¹H NMR (400 MHz, DMSO) δ2.55 (s, 3H), 7.81 (d, J=8, 1H), 7.92 (dd,J=2.8, 18.8, 1H), 8.11 (d, J=2.4, 1H).

APCIMS 311 [M−1]⁻

EXAMPLE 6K (2,5-Diphenyl-2H-1,2,3-triazole-4-carbonyl)guanidine

88% yield

¹H NMR (400 MHz, DMSO) δ7.41 (m, 4H), 7.52 (m, 2H), 7.90 (m, 2H), 8.04(m, 2H).

APCIMS 307 [M+1]⁺

EXAMPLE 6L[2-(3,5-Dichlorophenyl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidine

90% yield

¹H NMR (400 MHz, DMSO) δ2.54 (s, 3H), 7.63 (s, 1H), 7.89 (s, 2H).

APCIMS 313 [M+1]⁺

EXAMPLE 6M [2-(m-Tolyl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidine

92% yield

¹H NMR (400 MHz, DMSO) δ2.35 (s, 3H), 2.51 (s, 3H), 7.16 (m, 1H), 7.37(m, 1H), 7.83 (m, 2H).

APCIMS 259 [M+1]⁺

EXAMPLE 6N(2-(3-Chlorophenyl)-5-methyl-2H-1,2,3-triazole-4-carbonyl)guanidine

92% yield

¹H NMR (400 MHz, DMSO) δ2.54 (s, 3H), 7.46 (m, 1H), 7.56 (m, 1H), 7.91(m, 2H).

APCIMS 279 [M+1]⁺

EXAMPLE 6O [2-Phenyl-5-(n-propyl)-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

83% yield

¹H NMR (400 MHz, CD₃OD) δ1.02 (t, J=7, 3H), 1.81 (m, 2H), 3.15 (m, 2H),7.48 (m, 1H), 7.50 (m, 2H), 8.15 (m, 2H).

APCIMS 273 [M+1]⁺

EXAMPLE 6P (2-Phenyl-5-ethyl-2H-1,2,3-triazole-4-carbonyl)guanidinehydrochloride

79% yield

¹H NMR (400 MHz, CD₃OD) δ1.36 (t, J=8.4, 3H), 7.15 (m, 2H), 7.48 (m,1H), 7.55 (m, 2H), 8.16 (m, 2H).

APCIMS 259 [M+1]⁺

EXAMPLE 6Q (2-Phenyl-2H-1,2,3-triazole-4-carbonyl)guanidine

82% yield

¹H NMR (400 MHz, DMSO) δ7.30 (m, 1H), 7.57 (m, 2H), 8.01 (m, 2H), 8.19(s, 1H).

APCIMS 231 [M+1]⁺

EXAMPLE 6R[2-(3-Trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

94% yield

¹H NMR (400 MHz, CD₃OD) δ2.66 (s, 3H), 7.81 (d, J=4.8, 2H), 8.41 (m,2H).

APCIMS 313 [M+1]⁺

EXAMPLE 6S[2-(1-Naphthalenyl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

93% yield

¹H NMR (400 MHz, CD₃OD) δ2.61 (s, 3H), 7.61 (m, 3H), 7.82 (d, J=6, 1H),7.97 (m, 1H), 8.02 (m, 1H), 8.10 (d, J=8, 1H).

APCIMS 295 [M+1]⁺

EXAMPLE 6T[2-(8-Quinolinyl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

6% yield

¹H NMR (400 MHz, CD₃OD) δ2.64 (s, 3H),. 7.61 (m, 1H), 7.73 (t, J=7.8,1H), 7.96 (dd, J=1.4, 7.4, 1H), 8.13 (dd, J=1.4, 4.2, 1H), 8.45 (dd,J=1.8, 8.6, 1H), 8.86 (dd, J=1.6,4.4, 1H).

APCIMS 296 [M+1]⁺

EXAMPLE 6U[2-(3-Bromophenyl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

89% yield

¹H NMR (400 MHz, CD₃OD) δ2.63 (s, 3H), 7.50 (t, J=8.2, 1H), 7.64 (dd,J=2.0,1, 1H), 8.12 (m, 1H), 8.34 (t, J=2,1H).

APCIMS 323 [M+1]⁺

EXAMPLE 6V[5-(N,N-Dimethylcarbamoyl)-2-phenyl-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

80% yield

¹H NMR (400 MHz, CD₃OD) δ3.08 (s, 3H), 3.19 (s, 3H), 7.59 (m, 3H), 8.18(m, 2H).

APCIMS 302 [M+1]⁺

EXAMPLE 7(2-Phenyl-5-hydroxymethyl-2H-1,2,3-triazole-4-carbonyl)guanidinehydrochloride

A solution of guanidine hydrochloride (1.15 g, 12.0 mmol) in methanol (5mL) at 23° C. and under a nitrogen atmosphere was treated in one portionwith sodium methoxide (0.65 g, 12 mmol). The resulting suspension wasstirred for 1 h and filtered. The filtrate was concentrated in vacuo.The residue was dissolved in ethanol (10 mL) and added to2-phenyl-5-hydroxymethyl-2H-1,2,3-triazole-4-carboxylic acid lactone(0.41 g, 2.0 mmol) (Pollet, P.; Gelin, S. Synthesis 1979, 977) at 23° C.The resulting solution was stirred for 15 min and concentrated in vacuo.The residue was triturated with water and filtered. The solid wasair-dried to afford 0.43 g (81% yield) of the free base corresponding tothe title compound. This material in 5 ml methanol was treated withhydrogen chloride (4 M in dioxane, 2 ml, excess) for 1 hr at 23° C. andconcentrated in vacuo to afford the title compound (0.48 g, 79% yield).

¹H NMR (400 MHz, DMSO-d₆) δ8.74 (bs, 2H), 8.59 (bs, 2H), 8.16 (d, J=7.6,2H), 7.62 (t, J=8.0, 2H), 7.52 (t, J=7.4, 1H), 4.83 (s, 2H),

APCIMS 261 [M+1]⁺

EXAMPLE 8A (5-Methyl-1-phenyl-1H-1,2,3-triazole-4-carbonyl)guanidinehydrochloride

5-Methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid ethyl ester (333mg, 1.44 mmol) was reacted with guanidine (7.9 mmol), obtained as inExample 5, in 10 mL of methanol at reflux. After 16 hours, the mixturewas concentrated in vacuo, the residue taken up in ice water andextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated in vacuo. Theproduct was purified by silica gel chromatography eluting with 10%methanol in methylene chloride to afford 63 mg of the desiredacylguanidine. Transformation to the hydrochloride salt in the mannerdescribed in Example 7 afforded the title compound.

¹H NMR (DMSO-d₆) δ2.54 (s, 3H), 7.6-7.7 (m, 5H), 8.5 (bs, 2H), 8.7 (bs,2H), 11.6 (bs, 1H).

APCIMS 245 [M+1]⁺

The title compound of Example 8B was prepared using a procedureanalogous to that used for Example 8A.

EXAMPLE 8B (4-Methyl-5-phenyl-4H-1,2,4-triazole-3-carbonyl)guanidinehydrochloride

¹H NMR (DMSO-d₆) δ3.9 (s, 3H), 7.6 (m, 3H), 7.8 (m, 2H), 8.5 (bs, 2H),8.9 (bs, 2H), 11.8 (bs, 1H).

APCIMS 245 [M+1]⁺

The title compounds of Examples 9A-9N were prepared using proceduresanalogous to that described in Bajnati, A.; Kokel, B.; Hubert-Habart, M.Bull. Soc. Chim. Fr. 1987, 318.

EXAMPLE 9A Ethyl 3-methyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate

3% yield.

¹H NMR (CDCl₃) δ1.36 (t, 3H); 2.54 (s, 3H); 3.84 (s, 3H); 4.3 (q, 2H);6.96 (d, 2H); 7.56 (d, 2H); 8.23 (s, 1H).

EXAMPLE 9B Ethyl 5-methyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate

6% yield.

¹H NMR (CDCl₃) δ1.33 (t, 3H); 2.48 (s, 3H); 3.81 (s, 3H); 4.27 (q, 2H);6.94 (q, 2H); 7.26 (q, 2H); 7.96 (s, 1H).

EXAMPLE 9C Ethyl5-methyl-1-(4-sulfamoylphenyl)-1H-pyrazole-4-carboxylate

77% yield.

¹H NMR (DMSO-d₆) δ1.28 (t, 3H); 2.56 (s, 3H); 4.25 (q, 2H); 7.52 (s,2H)); 7.78 (d, 2H); 7.96 (d, 2H); 8.05 (s, 1H).

EXAMPLE 9D Ethyl5-methyl-1-(4-trifluoromethoxyphenyl)-1H-pyrazole-4-carboxylate

32% yield.

¹H NMR (CDCl₃) δ1.37 (t, 3H); 2.58 (s, 3H); 4.32 (q, 2H); 7.34 (q, 2H);7.46 (q, 2H); 8.03 (s, 1H).

EXAMPLE 9E Ethyl 5-methyl-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxylate

63% yield.

¹H NMR (CDCl₃) δ1.34 (t, 3H); 2.34 (s, 3H); 3.77 (s, 3H); 4.3 (q, 2H);7.02 (m, 2H); 7.28 (q, 1H); 7.41 (m, 1H); 8.01 (s, 1H).

EXAMPLE 9F Ethyl5-methyl-1-(4-methylsulfonylphenyl)-1H-pyrazole-4-carboxylate

46% yield.

¹H NMR (CDCl₃) δ1.35 (t, 3H);6.63 (s, 3H); 3.08 (s, 3H); 4.3 (q, 2H);7.65 (d, 2H); 8.05 (d, 2H); 8.08 (s, 1H).

EXAMPLE 9G Ethyl 5-methyl-1-(2-pyridyl)-1H-pyrazole-4-carboxylate

50% yield.

¹H NMR (DMSO-d₆) δ1.28 (t, 3H); 2.78 (s, 3H); 4.24 (q, 2H); 7.43-7.47(m, 1H); 7.78 (m, 12H); 8.02 (m, 2H); 8.53 (m 1H).

EXAMPLE 9H Ethyl 5-methyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylate

6% yield.

¹H NMR (DMSO-d₆) δ1.27 (t, 3H); 2.27 (s, 3H); 4.25 (q, 2H); 7.55 (m,1H); 7.60 (m, 1H); 7.74 (d, 1H); 7.89 (t, 1H); 8.1 (s, 1H); 8.2 (d, 1H);8.97 (m, 1H).

EXAMPLE 9I Ethyl 5-methyl-1-(4-pyridyl)-1H-pyrazole-4-carboxylate

22% yield.

¹H NMR (DMSO-d₆) δ1.27 (t, 3H); 2.64 (s, 3H); 4.23 (q, 2H); 7.64 (d,2H); 8.09 (s, 1H); 8.73 (d, 2H).

EXAMPLE 9J Ethyl 5-methyl-1-(3-methoxylphenyl)-1H-pyrazole-4-carboxylate77% yield

¹H NMR (DMSO-d₆) δ1.26 (t, 3H); 2.49 (s, 3H); 3.78 (s, 3H); 4.22 (q,2H); 7.03-7.08 (m, 3H); 7.42 (t, 1H); 7.97 (s, 1H).

EXAMPLE 9K Ethyl 5-methyl-1-(1-phthalazinyl)-1H-pyrazole-4-carboxylate

43% yield.

¹H NMR (DMSO-d₆) δ1.28 (t, 3H); 2.51 (s, 3H); 4.25 (q, 2H); 7.89 (d,1H); 8.09 (q, 1H); 8.1 (q, 1H); 8.19 (s, 1H); 8.32 (d, 1H); 9.84 (s,1H).

EXAMPLE 9L Ethyl 5-methyl-1-(4-quinolinyl)-1H-pyrazole-4-carboxylate andEthyl 3-methyl-1-(4-quinolinyl)-1H-pyrazole-4-carboxylate

68% yield.

¹H NMR (DMSO-d₆) δ1.19, 1.25 (2t, 3H); 2.33 (s, 3H); 4.06, 4.25 (2q,2H); 7.41, 7.70 (2d, 1H); 7.61, 7.82 (2t, 1H); 8;15 (m, 2H); 9.06 (d,1H).

EXAMPLE 9M Ethyl 5-methyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylate

40% yield.

¹H NMR (DMSO-d₆) δ1.26 (t, 3H); 2.57 (s, 3H); 4.22 (q, 2H); 7.61 (m,1H); 7.89 (d, 1H); 8.04 (s, 1H); 8.16 (d, 1H); 8.19 (s, 1H); 8.43 (d,1H); 8.96 (d, 1H).

EXAMPLE 9N Ethyl1-(2-bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

78% yield

¹H NMR (400 MHz, CDCl₃) δ0.80 (bs, 4H), 1.36 (t, J=7.2, 3H), 1.87 (m,1H), 4.30 (q, J=7.2, 2H), 7.41 (m, 3H), 7.71 (dd, J=1.4, 8, 1H), 8.03(s, 1H).

APCIMS 335 [M+1]⁺, 337 [M+3]⁺

The title compounds of Example 10A-10K were prepared using proceduresanalogous to that described in Menozzi, G.; Mosti, L.; Schenone, P. J.Heterocycl. Chem., 1987, 24, 1669.

EXAMPLE 10A Ethyl5-cyclopropyl--(2,6-dichlorophenyl)-1H-pyrazole-4-carboxylate

92% yield.

APCIMS 325 [M+1]⁺

¹H NMR (CDCl₃) δ1.77-1.84 (m, 1H), 8.07 (s, 1H).

EXAMPLE 10B Ethyl 5-methyl-1-(naphthalen-1-yl)-1H-pyrazole-4-carboxylate

66% yield.

APCIMS 281 [M+1]⁺

¹H NMR (CDCl₃) δ2.31 (s, 3H), 8.14 (s, 1H).

EXAMPLE 10C Ethyl 5-methyl-1-(quinolin-8-yl)-1H-pyrazole-4-carboxylate

66% yield.

APCIMS 282 [M+1]⁺

¹H NMR (CDCl₃) δ2.33 (m, 3H), 8.13 (s, 1H).

EXAMPLE 10D Ethyl5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carboxylate

89% yield.

APCIMS 308 [M+1]⁺

¹H NMR (CDCl₃) δ1.81-1.88 (m, 1H), 8.10 (s, 1H).

EXAMPLE 10E Ethyl5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate

88% yield.

APCIMS 308 [M+1]⁺

¹H NMR (CDCl₃) δ.8.95 (dd, J=1.8, 4.2, 1H), 8.24 (d, J=8.8, 1H), 8.10(s, 1H), 7.79 (t, J=7.8, 1H), 7.72 (dt, J=8.4, 0.8, 1H), 7.58 (d, J=7.2,1H), 7.41 (m, 1H), 4.31 (q, J=7.2, 2H), 1.76 (m, 1H), 1.37 (t, J=7.2,3H), 0.67 (m, 4H).

EXAMPLE 10F Ethyl5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carboxylate

82% yield.

APCIMS 308 [M+1]⁺

NMR (CDCl₃) δ1.80-1.87 (m, 1H), 8.09 (s, 1H).

EXAMPLE 10G Methyl 5-ethyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate

30% yield.

APCIMS 280 [M−1]⁻

¹H NMR (CDCl₃) δ0.94-0.97 (t, 3H), 8.10 (s, 1H).

EXAMPLE 10H Ethyl5-cyclopropyl-1-(isoquinolin-8-yl)-1H-pyrazole-4-carboxylate

24% yield.

APCIMS 308 [M+1]⁺

¹H NMR (CDCl₃) δ3.25-3.31 (m, 1H), 9.57 (s, 1H).

EXAMPLE 10J Ethyl5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate

88% yield.

APCIMS 325 [M+1]⁺

¹H NMR (CDCl₃) δ1.70-1.77 (m, 1H), 8.00 (s, 1H);

EXAMPLE 10K Ethyl 5-cyclopropyl-1-phenyl-1H-pyrazole-4-carboxylate

89% yield.

APCIMS 257 [M+1]⁺

¹H NMR (CDCl₃) δ1.87-2.00 (m, 1H), 8.00 (s, 1H).

EXAMPLE 11 Ethyl 2-methyl-5-phenyl-2H-pyrazole-3-carboxylate (Example11A) and Ethyl 1-methyl-5-phenyl-1H-pyrazole-3-carboxylate (Example 11B)

The lithium salt of ethyl 2,4-dioxo4-phenyl-butyrate (Murray, W. V.;Wachter, M. P. J. Heterocycl. Chem. 1989, 26, 1389) (1.0 g, 4.4 mmol)was combined in 4 mL absolute ethanol with methyl hydrazine (0.2 g, 4.4mmol), and hydrochloric acid (1.2 mL of a 4 N solution in dioxane, 4.8mmol). After heating the mixture at reflux for 2 h, the solution wasconcentrated in vacuo and the residue purified by silica gelchromatography using 5-20% ethyl acetate in hexanes as eluant to provideearlier eluting Example 11A (0.32 g, 31%) and later eluting Example 11 B(0.38 g, 38%).

EXAMPLE 11A Ethyl 2-methyl-5-phenyl-2H-pyrazole-3-carboxylate

¹H NMR (CD₃OD) δ1.4 (t, 3H), 4.15 (s, 3H), 4.3 (q, 2H), 7.2 (s, 1H), 7.3(t, 1H), 7.4 (t, 2H), 7.8 (d, 2H).

APCIMS 231 [M+1]⁺

EXAMPLE 11B Ethyl 1-methyl-5-phenyl-1H-pyrazole-3-carboxylate

¹H NMR (CD₃OD) δ1.4 (t, 3H), 3.9 (s, 3H), 4.3 (q, 2H), 6.8 (s, 1H),7.4-7.5 (m, 5H).

APCIMS 231 [M+1]⁺

The title compounds of Example 12A-12B were prepared using proceduresanalogous to that described in Bajnati, A.; Hubert-Habart, M. Bull. Soc.Chim. Fr. 1988, 540.

EXAMPLE 12A n-Butyl 3-methyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate

A mixture of 5-acetyluracil (0.231 g, 1.5 mmol), 5-quinolinylhydrazinedihydrochloride (0.418 g, 1.8 mmol) and HCl (conc., 0.75 mL, 9 mmol) inn-butanol (15 mL) was heated at reflux for 20 h, cooled to 23° C., andconcentrated in vacuo. The residue was dissolved in n-butanol (10 mL).The resulting solution was treated with H₂SO₄ (conc., 0.96 mL, 18 mmol),heated at reflux for 20 h, cooled to 23° C. and concentrated in vacuo.The residue was partitioned between EtOAc and NaOH (1 M). The aqueouslayer was extracted three times with EtOAc. The combined organicextracts were dried over Na₂SO₄ and concentrated in vacuo. The brownsolid residue was purified by flash chromatography (Flash 40S,hexanes-acetone 8:2) to afford 0.279 g (60%) of the desired product as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ0.96 (t, J=7, 3H), 1.45 (sextuplet, J=7.2, 2H),1.72 (quintet, J=6.8, 2H). 2.60 (s, 3H), 4.28 (quartet, J=6.6, 2H), 7.24(s, 1H), 7.47 (ddd, J=0.8, 4.4, 8.8, 1H), 7.58 (d, J=7.2, 1H), 7.76 (t,J=8, 1H), 8.21 (m, 1H), 8.30 (d, J=8, 1H), 8.98 (dd, J=1.4, 3, 1H).

APCIMS 310 [M+1]⁺

The title compound of Example 12B was prepared using a procedureanalogous to that used for Example 12A.

EXAMPLE 12B n-Butyl1-(isoquinolin-5-yl)-3-methyl-1H-pyrazole-4-carboxylate

43% yield

¹H NMR (400 MHz, CDCl₃) δ0.94 (t, J=7.4, 3H), 1.44 (sextuplet, J=7.6,2H), 1.70 (quintuplet, J=6.8, 2H), 2.58 (s, 3H), 4.26 (t, J=6.6, 2H),7.66 (t, J=7.7, 1H), 7.75 (m, 2H), 8.05 (d, J=8, 1H), 8.21 (s, 1H), 8.57(d, J=6, 1H), 9.33 (s, 1H).

APCIMS 310 [M+1]⁺

EXAMPLE 13A 5-Methyl-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxylic acid

To a solution of ethyl5-methyl-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxylate in 15 ml methanoland 17 ml water was added 20 ml of 1 N sodium hydroxide and theresulting mixture was refluxed overnight under nitrogen. The methanolwas removed in vacuo and the aqueous phase was acidified with diluteaqueous hydrochloric acid solution and extracted with 2×70 ml ethylacetate. The combined ethyl acetate extracts were washed with 70 mlwater and 70 ml brine, dried over sodium sulfate and concentrated invacuo to a white solid (2.14 g, 85% yield).

¹H NMR (CDCl₃) δ2.37 (s, 3H); 3.79 (s, 3H); 7.04 (q, 2H); 7.3 (d, 1H);7.44 (m, 1H); 8.09 (s, 1H).

The title compounds of Examples 13B-13Z were prepared using proceduresanalogous to that used for Example 13A.

EXAMPLE 13B 3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid

57% yield.

¹H NMR (DMSO-d₆) δ2.39 (s, 3H); 3.77 (s, 3H); 7.01 (d, 2H); 7.76 (d,2H): 8,72 (s, 1H).

EXAMPLE 13C 5-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid

91% yield.

¹H NMR (DMSO-d₆) δ2.43 (s, 3H); 3.81 (s, 3H); 7.08 (d, 2H); 7.41 (d,2H); 7.9 (s, 1H); 12.4 (s, 1H).

EXAMPLE 13D 5-Methyl-1-(4-sulfamoylphenyl)-1H-pyrazole-4-carboxylic acid

51 % yield.

¹H NMR (DMSO-d₆) δ2.46 (s, 3H); 7.48 (s, 2H); 7.72 (d, 2H); 7.92 (d,2H); 7.98 (s, 1H).

EXAMPLE 13E 5-Methyl-1-(4-trifluoromethoxyphenyl)-1H-pyrazole-4-carboxylic acid

91% yield.

¹H NMR (DMSO-d₆) δ2.45 (s, 3H); 7.53 (t, 1H); 7.65 (m, 2H); 7.95 (s,1H); 12.5 (s, 1H).

EXAMPLE 13F 5-Methyl-1-(4-methylsulfonyl)-1H-pyrazole-4-carboxylic acid

82% yield.

¹H NMR (DMSO-d₆) δ2.55 (s, 3H); 3.26 (s, 3H); 7.81 (d, 2H); 7.83 (s,1H); 8.02 (d, 2H); 12.5 (s, 1H).

EXAMPLE 13G Methyl-1-(2-pyridyl)-1H-pyrazole-4-carboxylic acid

91% yield.

¹H NMR (DMSO-d₆) δ2.78 (s, 3H); 7.45 (q, 1H); 7.77 (d, 1H); 7.95-8.05(m, 2H); 8.53 (d, 1H); 12.55 (s, 1H).

EXAMPLE 13H 5-Methyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylic acid

75% yield.

¹H NMR (DMSO-d₆) δ2.27 (s, 3H); 7.56 (m, 1H); 7.62 (m, 1H); 7.77 (d,1H); 7.91 (t, 1H); 8.07 (s, 1H); 8.21 (d, 1H); 8.99 (m, 1H).

EXAMPLE 13I 5-Methyl-1-(4-pyridyl)-1H-pyrazole-4-carboxylic acid

3% yield.

¹H NMR (DMSO-d₆) δ2.62 (s, 3H); 7.61 (q, 2H); 7.95 (s, 1H); 8.68 (q,2H).

EXAMPLE 13J 5-Methyl-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxylic acid

98% yield.

¹H NMR (DMSO-d₆) δ2.46 (s, 3H); 3.76 (s, 3H); 7.04 (m, 3H); 7.41 (m,1H); 7.91 (s, 1H); 12.4 (s, 1H).

EXAMPLE 13K 5-Methyl-1-(1-phthalazinyl)-1H-pyrazole-4-carboxylic acid

84% yield.

¹H NMR (DMSO-d₆) δ2.57 (s, 3H); 7.88 (d, 1H); 8.07-8.18 (m, 3H); 8.34(d, 1H); 9.86. (s, 1H).

EXAMPLE 13L 5-Methyl-1-(4quinolinyl)-1H-pyrazole-4-carboxylic acid

66% yield.

¹H NMR (DMSO-d₆) δ2.31 (s, 3H); 7.42 (d, 1h); 7.62 (dd, 1H); 7.7 (d,1H); 7.83 (t, 1H); 8.10 (d and s, 2H); 9.06 (d, 1H); 12.5 (bs, 1H).

EXAMPLE 13M 5-Methyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylic acid

84% yield.

¹H NMR (DMSO-d₆) δ2.63 (s, 3H); 7.66 (m, 1H); 7.98 (d, 1H); 8.07 (s,1H); 8.22 (m, 2H); 8.48 (d, 1H); 9.02 (d, 1H).

EXAMPLE 13N 4-Methyl-1-phenyl-1H-pyrazole-3-carboxylic acid

¹H NMR (CDCl₃) δ2.4 (s, 3H), 7.4 (t, 1H), 7.5 (t, 2H), 7.7 d, 2H), 7.8(s, 1H).

APCIMS 203 [M+1]⁺

EXAMPLE 13O 3-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid

¹H NMR (CD₃OD) δ2.5 (s, 3H), 7.4 (t, 1H), 7.5 (t, 2H), 7.8 (d, 2H), 8.6(s, 1H).

APCIMS 203 [M+1]⁺

EXAMPLE 13P 5-Cyclopropyl-1-phenyl-1H-pyrazole-4-carboxylic acid

94% yield.

APCIMS 227 [M−1]⁻

¹H NMR (DMSO-d₆) δ1.99-2.06 (m, 1H), 7.88 (s, 1H).

EXAMPLE 13Q5-Cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carboxylic acid

99% yield.

APCIMS 295 [M−1]⁻

¹H NMR (DMSO-d₆) δ1.73-1.80 (m, 1H), 7.98 (s, 1H).

EXAMPLE 13R 1-(2-Bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylicacid

93% yield

¹H NMR (400 MHz, DMSO-d₆) δ0.66 (bs, 4H), 1.82 (m, 1H), 7.50 (m, 3H),7.80 (dd, J=1.2, 7.6, 1H), 7.89 (s, 1H), 12.33 (s, 1H).

APCIMS 307 [M+1]⁺, 309 [M+3]⁺

EXAMPLE 13S 5-Methyl-1-(naphthalen-1-yl)-1H-pyrazole-4-carboxylic acid

79% yield

APCIMS 251 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.22 (s, 3H), 7.09-7.11 (d, 1H).

EXAMPLE 13T 5-Methyl-1-(quinolin-8-yl)-1H-pyrazole-4-carboxylic acid

65% yield.

APCIMS 252 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.13 (s, 3H), 8.84-8.85 (d, 1H).

EXAMPLE 13U 5-Methyl-1-(isoquinolin-5-yl)-1H-pyrazole-4-carboxylic acid

45% yield.

APCIMS 252 [M−1]⁻

H NMR (DMSO-d₆) δ2.24 (s, 3H), 8.05 (s, 1H).

EXAMPLE 13V 5-Cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carboxylicacid

66% yield.

APCIMS 278 [M−1]⁻

¹H NMR (DMSO-d₆) δ1.69-1.76 (m, 1H), 7.97 (s, 1H).

EXAMPLE 13W 5-Cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylicacid

56% yield.

APCIMS 278 [M−1]⁻

¹H NMR (DMSO-d₆) δ8.94 (dd, J=1.6, 4.0, 1H), 8.15 (dd, J=0.8, 8.4, 1H),7.87 (s, 1H), 7.85-7.83 (m, 1H), 7.71 (dd, J=1.2, 7.2, 1H), 7.59-7.51(m, 2H), 1.79 (m, 1H), 0.69 (m, 2H), 0.51-0.47 (m, 2H).

EXAMPLE 13X5-Cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carboxylic acid

72% yield.

APCIMS 295 [M−1]⁻

¹H NMR (DMSO-d₆) δ1.71-1.78 (m, 1H), 7.89 (s, 1H).

EXAMPLE 13Y 5-Ethyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid

98% yield.

APCIMS 266 [M−1]⁻

¹H NMR (DMSO-d₆) δ0.75-0.79 (t, 3H), 8.94-8.94 (d, 1H).

EXAMPLE 14A 2-Methyl-5-phenyl-2H-pyrazole-3-carboxylic acid.

2-Methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.32 g,1.39 mmol) was dissolved in 4.5 mL of tetrahydrofuran, 1.5 mL ofmethanol and 1.5 mL of water, and treated with lithium hydroxide hydrate(0.12 g, 2.78 mmol). After stirring at room temperature overnight, themixture was acidified (pH =1) with hydrochloric acid, and extracted withethyl acetate (3×10 mL) and the combined organic phases washed with 10mL of brine. The organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo to afford a quantitative yield of thetitle compound.

¹H NMR (CD₃OD) δ4.2 (s, 3H), 7.2 (s, 1H), 7.3 (t, 1H), 7.4 (t, 2H), 7.8(d, 2H).

APCIMS 203 [M+1]⁺

The title compounds of Examples 14B-14D were prepared using a procedureanalogous to that used for Example 14A.

EXAMPLE 14B 1-Methyl-5-phenyl-1H-pyrazole-3-carboxylic acid

¹H NMR (CD₃OD) δ3.9 (s, 3H), 6.8 (s, 1H), 7.4-7.5 (m, 5H).

APCIMS 203 [M+1]⁺

EXAMPLE 14C 3-Methyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid

86% yield

¹H NMR (400 MHz, DMSO-d₆) δ2.45 (s, 3H), 7.60 (ddd, J=1.2, 4.0, 8.8,1H), 7.73 (d, J=7.6., 1H). 7.84 (t, J=8, 1H), 8.12 (d, J=8.4, 1H), 8.26(d, J=8.8, 1H), 8.59 (s, 1H), 8.97 (dd, J=1.2, 2.8, 1H), 8.98 (dd,J=1.4, 3, 1H).

APCIMS 252 [M−1]⁻

EXAMPLE 14D 1-(Isoquinolin-5-yl)-3-methyl-1H-pyrazole-4-carboxylic acid

97% yield

¹H NMR (400 MHz, DMSO-d₆) δ2.46 (s, 3H), 7.60 (m, 2H), 7.92 (d, J=7.2,1H), 8.25 (d, J=8, 1H), 8.56 (d, J=6, 1H), 8.64 (s, 1H), 9.44 (s, 1H),12.50 (bs, 1H).

APCIMS 252 [M−1]⁻

The title compounds of Examples 15A-15II were prepared using proceduresanalogous to that used for Example 6A.

EXAMPLE 15A[3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

34% yield.

¹H NMR (DMSO-d₆) δ2.42 (s, 3H); 3.76 (s, 3H); 7.08 (d, 2H); 7.63 (d,2H); 8.32 (bs, 2H); 8.43 (bs, 2H); 9.45 (s, 1H).

EXAMPLE 15B[5-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

24% yield.

¹H NMR (DMSO-d₆) δ2.49 (s, 3H); 3.82 (s, 3H); 7.08 (d, 2H); 7.44 (d,2H); 8.35 (bs, 2H); 8.63 (bs, 2H); 8.64 (s, 1H).

EXAMPLE 15C[5-Methyl-1-(4-sulfamoylphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

19% yield.

¹H NMR (DMSO-d₆) δ2.46 (s, 3H); 7.51 (s, 2H); 7.77 (d, 2H); 7.95 (d,2H); 8.31 (bs, 2H); 8.47 (bs, 2H); 8.58 (s, 1H).

EXAMPLE 15D[5-Methyl-1-(4-trifluoromethoxyphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

20% yield.

¹H NMR (DMSO-d₆) δ2.49 (s, 3H); 7.58 (d, 2H); 7.7 (d, 2H); 8.36 (bs,2H); 8.61 (bs, 2H); 8.69 (s, 1H); 11.75 (s, 1H).

EXAMPLE 15E[5-Methyl-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

27% yield.

¹H NMR (DMSO-d₆) δ2.27 (s, 3H); 3.76 (s, 3H); 7.1 (t, 1H); 7.27 (d, 1H);7.34 (d, 1H); 7.54t, 1H); 8.34 (bs, 2H); 8.62 (bs, 3H).

EXAMPLE 15F[5-Methyl-1-(4-methylsulfonyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

511% yield.

¹H NMR (DMSO-d₆) δ2.61 (s, 3H); 3.29 (s, 3H); 7.85 (d, 2H); 8.09 (d+s,3H); 8.4-8.7 (bd, 4H); 11.9 (s, 1H).

EXAMPLE 15G [5-Methyl-1-(2-pyridyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

60% yield.

¹H NMR (DMSO-d₆) δ2.8 (s, 3H); 7.51 (s, 1H); 7.83 (d, 1H); 8.07 (t, 1H);7.5-8.2 (bs, 2H); 8.44 (s, 1H); 8.56 (s, 1H); 8.71 (s, 1H); 8.8 (s, 1H);11.9 (s, 1H).

EXAMPLE 15H [5-Methyl-1-(5-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

53% yield.

¹H NMR (DMSO-d₆) δ2.31 (s, 3H); 7.59 (m, 1H); 7.68 (d, 1H); 7.79 (d,1H); 7.93 (t, 1H); 8.27 (d, 1H); 8.55 (bs, 2H); 8.81 (bs, 2H); 8.98 (s,1H); 9.00 (d, 1H).

EXAMPLE 15I [5-Methyl-1-(4-pyridyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

9% yield.

¹H NMR (DMSO-d₆) δ2.68 (s, 3H); 7.87 (d, 2H); 8.41 (bs, 2H); 8.67 (bs,2H); 8.86. (s and d, 3H).

EXAMPLE 15J[5-Methyl-1-(3-methoxyphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

57% yield.

¹H NMR (DMSO-d₆) δ2.5 (s, 3H); 3.77 (s, 3H); 7.07 (m, 3H); 7.43 (m, 1H);8.36 (bs, 2H); 8.66 (bs, 2H); 8.69 (s, 1H).

EXAMPLE 15K[5-Methyl-1-(1-phthalazinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

18% yield.

¹H NMR (DMSO-d₆) δ2.57 (s, 3H); 7.87 (d, 1H); 8.09 (q, 1H); 8.16 (q,1H); 8.36 (d, 1H); 8.49 (bs, 1H); 8.76 (bs, 2H); 9.90 (s, 1H).

EXAMPLE 15L [5-Methyl-1-(4-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

45% yield.

¹H NMR (DMSO-d₆) δ2.39 (s, 3H); 7.5 (d, 1H); 7.70 (t, 1H); 7.86 (d, 1H);7.92 (t, 1H), 8.23 (d, 1H); 8.5 (bs, 2H); 8.77 (bs, 2H); 9.01 (s, 1H);9.18 (s, 1H); 12.2 (s, 1H).

EXAMPLE 15M [5-Methyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

92% yield.

¹H NMR (DMSO-d₆) δ2.69 (s, 3H); 7.87 (m, 1H); 8.11 (d, 1H); 8.33 (d,1H); 8.42 (s, 1H); 8.46 (bs, 2H); 8.73 (bs, 2H); 8.79 (d, 1H); 8.88 (s,1H); 9.16 (d, 1H); 12.1 (s₁, H).

EXAMPLE 15N 5-Methyl-1-phenyl-1H-pyrazole-4-carbonyl)guanidinehydrochloride

62% yield.

¹H NMR (DMSO-d₆) δ2.49 (s, 3H); 7.52 (m, 5H); 8.34 (s, 2H); 8.63 (s,1H); 8.67 (s, 2H); 11.79 (s, 1H).

EXAMPLE 15O[1-(2-Bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

66% yield

¹H NMR (400 MHz, DMSO-d₆) δ0.59 (bs, 2H), 0.74 (d, J=7.6, 2H), 1.92 (m,1H), 7.55 (m, 3H), 7.85 (d, J=7.6, 1H), 8.41 (bs, 2H), 8.66 (s, 1H),8.70 (bs, 2H), 11.83 (s, 1H).

APCIMS 348 [M+1]⁺, 350 [M+3]⁺

EXAMPLE 15P (4-Methyl-1-phenyl-1H-pyrazole-3-carbonyl)guanidinehydrochloride

¹H NMR (CD₃OD) δ2.3 (s, 3H), 7.3 (t, 1H), 7.4 (t, 2H), 7.8 (d, 2H), 8.0(s, 1H).

APCIMS 244 [M+1]⁺

EXAMPLE 15Q (5-Methyl-1-phenyl-1H-pyrazole-3-carbonyl)guanidinehydrochloride

¹H NMR (CD₃OD) δ2.4 (s, 3H), 7.4 (t, 1H), 7.5 (t, 2H), 7.8 (d, 2H), 8.2(s, 1H). 1H).

APCIMS 244 [M+1]⁺

EXAMPLE 15R [1-(4-Bromophenyl)-4-methyl-1H-pyrazole-3-carbonyl]guanidinehydrochloride

¹H NMR (CD₃OD) δ2.4 (s, 3H), 7.7 (d, 2H), 7.8 (d, 2H), 8.2 (s, 1H).

APCIMS 322 [M+1]⁺, 324 [M+3]⁺

EXAMPLE 15S [1-(4-Bromophenyl)-5-methyl-1H-pyrazole-3-carbonyl]guanidinehydrochloride

¹H NMR (CD₃OD) δ2.3 (s, 3H), 6.7 (s, ₁H), 7.4 (d, 2H), 7.7 (d, 2H).

APCIMS 322 [M+1]⁺, 324 [M+3]⁺

EXAMPLE 15T (1-Phenyl-1H-pyrazole-3-carbonyl)guanidine hydrochloride

¹H NMR (CD₃OD) δ6.9 (d, 1H, J 3 Hz), 7.3 (t, 1H), 7.5 (t, 2H), 7.8 (d,2H), 8.2 (d, 1H, J 3 Hz).

APCIMS 230 [M+1]⁺

EXAMPLE 15U (3-Methyl-1-phenyl-1H-pyrazole-4-carbonyl)guanidinehydrochloride

¹H NMR (DMSO-d6) δ2.4 (s, 3H), 7.4 (t, 1H), 7.6 (t, 2H), 7.8 (d, 2H),8.4 (bs, 2H), 8.5 (bs, 2H), 9.6 (s, 1H), 12.0 (s, 1H).

APCIMS 244 [M+1]⁺

EXAMPLE 15V (2-Methyl-5-phenyl-2H-pyrazole-3-carbonyl)guanidinehydrochloride

¹H NMR (DMSO-d₆) δ4.1 (s, 3H), 7.3 (s, 1H), 7.4 (t, 1H), 7.4 (t, 2H),7.7 (d, 2H), 8.5 (bs, 2H), 8.6 (bs, 2H), 11.4 (bs, 1H).

APCIMS 244 [M+1]⁺

EXAMPLE 15W (1-Methyl-5-phenyl-1H-pyrazole-3-carbonyl)guanidinehydrochloride

¹H NMR (DMSO-d₆) δ4.0 (s, 3H), 7.1 (s, 1H), 7.5-7.6 (m, 5H), 8.5 (bs,2H) 8.6 (bs, 2H), 12.1 (bs, 1H).

APCIMS 244 [M+1]⁺

EXAMPLE 15X[2-Methyl-5-(naphthalen-1-yl)-2H-pyrazole-3-carbonyl]guanidinehydrochloride

¹H NMR (DMSO-d₆) δ4.2 (s, 3H), 7.6 (m, 3H), 7.67 (d, 1H), 7.9 (s, 1H),8.0 (m, 2H), 8.5 (m, 3H), 8.6 (bs, 2H).

APCIMS 292 [M−1]⁻

EXAMPLE 15Y [5-(tert-Butyl)-2-methyl-2H-pyrazole-3-carbonyl]guanidinehydrochloride

¹H NMR (DMSO-d₆) δ1.2 (s, 9H), 4.0 (s, 3H), 7.4 (s, 1H), 8.4 (bs, 2H),8.6 (bs, 2H), 11.8 (bs, 1H).

APCIMS 224 [M+1]⁺

EXAMPLE 15Z (1,5-Diphenyl-1H-pyrazole-3-carbonyl)guanidine hydrochloride

¹H NMR (DMSO-d₆) δ7.2 (m, 2H), 7.3 (m, 4H), 7.4 (m, 2H), 7.5 (m, 3H),8.5 (bs, 4H).

APCIMS 306 [M+1]⁺

EXAMPLE 15AA (1,4-Dimethyl-5-phenyl-1H-pyrazole-3-carbonyl)guanidinehydrochloride

¹H NMR (DMSO-d₆) δ2.1 (s, 3H), 3.8 (s, 3H), 7.4-7.6 (m, 5H), 8.5 (bs,2H), 8.6 (bs, 2H), 11.1 (bs, 1H).

APCIMS 258 [M+1]⁺

EXAMPLE 15BB[3-Methyl-1-(naphthalen-1-yl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

¹H NMR (DMSO-d₆) δ2.5 (s, 3H), 7.6 (m, 4H), 7.75 (d, 1H, J =8 Hz), 8.1(m, 2H), 8.3 (bs, 2H), 8.4 (bs, 2H), 9.15 (s, 1H), 11.8 (s, 1H).

APCIMS 294 [M+1]⁺

EXAMPLE 15CC (2-Methyl-5-phenyl-2H-pyrazole-3-carbonyl)guanidinehydrochloride

¹H NMR (DMSO-d₆) δ4.1 (s, 3H), 7.3 (s, 1H), 7.4 (t, 1H), 7.4 (t, 2H),7.7 (d, 2H), 8.5 (bs, 2H), 8.6 (bs, 2H), 11.4 (bs, 1H).

APCIMS 244 [M+1]⁺

EXAMPLE 15DD (1-Methyl-5-phenyl-1H-pyrazole-3-carbonyl)guanidinehydrochloride

¹H NMR (DMSO-d₆) δ4.0 (s, 3H), 7.1 (s, 1H), 7.5-7.6 (m, 5H), 8.5 (bs,2H), 8.6 (bs, 2H), 12.1 (bs, 1H).

APCIMS 244 [M+1]⁺

EXAMPLE 15EE [5-(tert-Bulyl)-2-methyl-2H-pyrazole-3-carbonyl]guanidinehydrochloride

¹H NMR (DMSO-d₆) δ1.2 (s, 9H), 4.0 (s, 3H), 7.4 (s, 1H), 8.4 (bs, 2H),8.6 (bs, 2H), 11.8 (bs, 1H).

APCIMS 224 [M+1]⁺

EXAMPLE 15FF (1,5-Diphenyl-1H-pyrazole-3-carbonyl)guanidinehydrochloride

¹H NMR (DMSO-d₆) δ7.2 (m, 2H), 7.3 (m, 4H), 7.4 (m, 2H), 7.5 (m, 3H),8.5 (bs, 4H).

APCIMS 306 [M+1]⁺

EXAMPLE 15GG (1,4-Dimethyl-5-phenyl-1H-pyrazole-3-carbonyl)guanidinehydrochloride

¹H NMR (DMSO-d₆) δ2.1 (s, 3H), 3.8 (s, 3H), 7.4-7.6 (m, 5H), 8.5 (bs,2H), 8.6 (bs, 2H), 11.1 (bs, 1H).

APCIMS 258 [M+1]⁺

EXAMPLE 15HH[3-Methyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

23% yield

¹H NMR (400 MHz, CD₃OD) δ2.62 (s, 3H), 8.07 (m, 2H), 8.22 (t, J=7.8,1H), 8.36 (d, J=7.6, 1H), 9.12 (s, 1H), 9.20 (d, J=8.8, 1H), 9.27 (d,J=5.2, 1H).

APCIMS 296 [M+1]⁺

EXAMPLE 15II[1-(Isoquinolin-5-yl)-3-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

93% yield

¹H NMR (400 MHz, DMSO-d₆) δ2.49 (s, 3H),. 7.03 (s, 1H), 8.02 (m, 1H),8.18 (m, 2H), 8.58 (m, 6H), 9.50 (s, 1H), 9.82 (s 1H), 12.38 (s, 1H).

APCIMS 295 [M+1]⁺

EXAMPLE 16A[5-Cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

A mixture of 5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylicacid (4.08 g, 14.6 mmol) and 25 ml SOCl₂ was heated to reflux for 1hour. The excess SOCl₂ was removed in vacuo via codistillation withtoluene. The solid residue was added portionwise over 45 minutes to avigorously stirred 40° C. solution of guanidine hydrochloride (5.02 g,52.6 mmol) in 59 ml of 2 N NaOH and 29 ml THF. The resulting mixture washeated at reflux for 1 hour and then cooled to 23° C. The organicsolvent and 40 ml of the H₂O were removed in vacuo. The tan solid thatprecipitated was filtered and washed with 2×5 ml portions of cold H₂O.This solid was air-dried for 1 hour and then dried for 24 h under highvacuum at 40° C. to afford 3.5 g of the free base of the title compound.This solid was dissolved in 25 ml of hot methanol and treated with 1.85ml of conc. HCl. This pale yellow solution was stirred for 15 min atroom temperature and concentrated in vacuo to a light amber gum. Theresidual H₂O was removed in vacuo via codistillation with 3×25 mlportions of anhydrous ethanol. The resulting pale yellow solid wasrecrystallized from hot ethanol to afford 3.58 g of the title compound(62% yield).

APCIMS 319 [M−1]⁻

¹H NMR (DMSO-d₆) δ9.16 (m, 1H), 8.86 (s, 1H), 8.85 (bs, 2H), 8.50 (bs,2H), 8.37 (d, J=8.4, 1H), 8.08-7.97 (m, 3H), 7.78 (dd, J=4.4, 8.4, 1H),1.99-193 (m, 1H), 0.64-0.62 (m, 2H), 0.42 (m, 2H).

The title compounds of Examples 16B-16AA were prepared using proceduresanalogous to that used for Example 16A.

EXAMPLE 16B[1-(3,4-Dichlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

3% yield.

APCIMS 301 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.59 (s, 3H), 7.93 (s, 1H)

EXAMPLE 16C (1-Benzyl-5-methyl-1H-pyrazole-4-carbonyl)guanidinehydrochloride

24% yield.

APCIMS 256 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.48 (s, 3H), 8.84 (s, 1H)

EXAMPLE 16D [5-Methyl-1-(p-tolyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

29% yield.

APCIMS 256 [M −1]⁻

¹H NMR (DMSO-d₆) δ2.49 (s, 3H), 8.64 (s, 1H)

EXAMPLE 16E (5-Isopropyl-1-phenyl-1H-pyrazole-4-carbonyl)guanidinehydrochloride

42% yield.

APCIMS 270 [M−1]⁻

¹H NMR (DMSO-d₆) δ1.22 (d, 6H), 8.63 (s, 1H)

EXAMPLE 16F (1,5-Diphenyl-1H-pyrazole-4-carbonyl)guanidine hydrochloride17% yield.

APCIMS 304 [M−1]⁻

¹H NMR (DMSO-d₆) δ7.17-7.35 (m, 10H), 8.81 (s, 1H)

EXAMPLE 16G (5-Ethyl-1-phenyl-1H-pyrazole-4-carbonyl)guanidinehydrochloride

7% yield.

APCIMS 256 [M−1]⁻

¹H NMR (DMSO-d₆) δ1.01-1.06 (t, 3H), 8.64 (s, 1H)

EXAMPLE 16H [1-Phenyl-5-(n-propyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

4% yield.

APCIMS 270 [M−1]⁻

¹H NMR (DMSO-d₆) δ0.68-0.71 (t, 3H), 7.08 (s, 1H)

EXAMPLE 16I[1-(3,5-Dichlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

6% yield.

APCIMS 311 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.57 (s, 3H), 8.7 (s, 1H)

EXAMPLE 16J[1-(2-Chlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

22% yield.

APCIMS 276 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.30 (s, 3H), 8.68 (s, 1H)

EXAMPLE 16K[5-Methyl-1-(3-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

53% yield.

APCIMS 310 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.45 (s, 1H), 8.76 (s, 1H)

EXAMPLE 16L[1-(3-Chlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

6% yield.

APCIMS 276 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.54 (s, H), 8.67 (s, 1H)

EXAMPLE 16M[5-Methyl-1-(naphthalen-1-yl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

8% yield.

APCIMS 292 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.26 (s, 3H), 8.65 (s, 1H)

EXAMPLE 16N[1-(4-Chlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

60% yield.

APCIMS 276 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.52 (s, 3H), 8.71 (s, 1H)

EXAMPLE 16O[5-Methyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

82% yield.

APCIMS 310 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.28 (s, 3H), 8.65 (s, 1H)

EXAMPLE 16P (3,5-Dimethyl-1-phenyl-1H-pyrazole-4-carbonyl)guanidinehydrochloride

1% yield.

APCIMS 256 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.38 (s, 3H), 2.42 (s, 3H)

EXAMPLE 16Q (1-Cyclohexyl-5-methyl-1H-pyrazole-4-carbonyl)guanidinehydrochloride

59 % yield.

APCIMS 248 [M−1]

¹H NMR (DMSO-d₆) δ2.50 (s, 3H), 8.41 (s, 1H)

EXAMPLE 16R [5-Methyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

60% yield.

APCIMS 293 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.22 (s, 3H), 8.75 (s, 1H)

EXAMPLE 16S[1-(2,6-Dichlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

33% yield.

APCIMS 311 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.27 (s, 3H), 8.76 (s, 1H)

EXAMPLE 16T[5-Cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

70% yield.

APCIMS 336 [M−1]⁻

¹H NMR (DMSO-d₆) δ1.83-1.90 (m, 1H), 8.57 (s, 1H)

EXAMPLE 16U[1-(Isoquinolin-5-yl)-5-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

51% yield.

APCIMS 293 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.33 (s, 3H), 8.98 (s, 1H)

EXAMPLE 16V[1-(2,3-Dichlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

39% yield.

APCIMS311 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.32 (s, 3H), 8.78 (s, 1H)

EXAMPLE 16W [5-Cyclopropyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

22% yield.

APCIMS 268 [M−1]⁻

¹H NMR (DMSO-d₆) δ2.11-2.17 (m, 1H), 8.56 (s, 1H)

EXAMPLE 16X[1-(3-Chlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

A mixture of 5-methyl-1-(3-chlorophenyl)pyrazole-4-carboxylic acid (234mg, 1.0 mmol) and 5 ml SOCl₂ was heated to reflux for 45 min. ExcessSOCl₂ was removed in vacuo via codistillation with toluene. The residuewas dissolved in 2mL of anhydrous THF and added dropwise over 30 minutesto a vigorously stirred 40° C. solution of guanidine hydrochloride (344mg, 3.6 mol) in 3.25 mL 2 N NaOH and 1.9 mL THF. The resulting mixturewas heated to reflux for 4 hours and then cooled. The organic solventwas removed in vacuo. The residue was diluted with 10 mL 1 N NaOH andextracted with 5×5 mL EtOAc. The combined organic layers were dried(Na₂SO₄) filtered and concentrated in vacuo to a white solid. Thismaterial was dissolved in 1 mL MeOH and 18.4 μL 12 N HCl was added withstirring. The solvents were removed in vacuo with toluene azeotropes andthe resulting solid was stirred in 1 mL ether/acetone (1:1) and filteredto remove residual H₂O. Drying under high vacuum at 40° C. afforded thedesired product (20 mg, 6%).

APCIMS 276 [M−1]⁻;

¹H NMR (DMSO-d₆) δ2.54 (s, 3H) 8.68 (s, 1H).

EXAMPLE 16Y[5-Cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

61% yield.

APCIMS 337 [M−1]⁻

¹H NMR (DMSO-d₆) δ1.82-1.89 (m, 1H), 8.65 (s, 1H)

EXAMPLE 16Z[5-Cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

APCIMS 319 [M−1]⁻

¹H NMR DMSO-d₆) δ1.77-1.84 (m, 1H), 8.87(s, 1H).

Yield of HCl salt 3.5%

EXAMPLE 16AA [5-Ethyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

14% yield.

APCIMS 307 [M−1]⁻

¹H NMR (DMSO-d₆) δ0.86-0.89 (t, 3H), 8.93 (s, 1H).

The title compound of Example 17 was prepared using a procedureanalogous to that described in Klinsberg, E. Synthesis 1972, 475, andExample 3A.

EXAMPLE 17 2-(Naphthalen-2-yl)-5-methyl-2H-1,2,3-triazole-4-carboxylicacid

52% yield

¹H NMR (400 MHz, DMSO-d₆) δ2.52 (s, 3H), 7.55 (m, 2H), 7.96 (d, J=8,1H), 8.12 (m, 3H), 8.53 (s, 1H).

APCIMS 252 [M−1]⁻

The title compound of Example 18 was prepared using a procedureanalogous to that used for Example 16A.

EXAMPLE 18[2-(Naphthalen-2-yl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidinehydrochloride

94% yield

¹H NMR (400 MHz, DMSO-d₆) δ2.54 (s, 3H), 7.11 (m, 1H), 7.56 (m, 3H),8.10 (m, 4H), 8.29 (m, 2H), 8.63 (m, 2H).

APCIMS 295 [M+1]⁺

The title compounds of Examples 19A-19OOO were prepared using proceduresanalogous to that described in Menozzi, G.; Mosti, L.; Schenone, P. J.Heterocycl. Chem., 1987, 24, 1669.

EXAMPLE 19A Ethyl5-cyclopropyl-1-(2,3-dimethoxyphenyl)-1H-pyrazole-4-carboxylate

89% yield.

APCIMS 317 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.66-0.88 (m, 4H), 1.36 (t, J=7.2, 3H), 1.93(m, 1H), 3.60 (s, 3H), 3.92 (s, 3H), 4.30 (q, J=7.2, 2H0, 6.93 (d, J=8,1H), 7.02 (d, J=8.4, 1H), 7.13 (t, J=8, 1H), 8.01 (s, 1H).

EXAMPLE 19B Ethyl5-cyclopropyl-1-(naphthalen-1-yl)-1H-pyrazole-4-carboxylate

72% yield.

APCIMS 307 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.6-0.8 (m, 4H), 1.39 (t, J=7.2, 3H), 1.80 (m,1H), 4.33 (q, J=7.2, 2H), 7.30 (d, J=7.6, 1H), 7.52 (m, 4H), 7.92 (d,J=8, 1H), 7.98 (d, J=7.6, 1H), 8.12 (s, 1H).

EXAMPLE 19C Ethyl5-cyclopropyl-1-(naphthalen-2-yl)-1H-pyrazole-4-carboxylate

96% yield.

APCIMS 307 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.64 (m, 2H), 0.91 (m, 2H), 1.39 (m, 3H), 2.07(m 1H), 4.33 (m, 2H), 7.25 (m, 1H), 7.56 (m, 2H), 7.66 (m, 1H), 8.06 (m,4H).

EXAMPLE 19D Ethyl 5-cyclopropyl-1-(o-biphenyl)-1H-pyrazole-4-carboxylate

57% yield.

APCIMS 333 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.46 (m, 4H), 0.99 (m, 1H), 1.28 (m, 3H), 4.19(m, 2H), 7.03 (m, 2H), 7.22 (m, 3H), 7.41-7.53 (m, 4H), 7.97 (s, 1H).

EXAMPLE 19E Ethyl5-cyclopropyl-1-(2-nitrophenyl)-1H-pyrazole-4-carboxylate

51 % yield.

APCIMS 302 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.68 (m, 2H), 0.86 (m, 2H), 1.36 (m, 3H), 1.82(m, ₁H), 4.32 (m, 2H), 7.55-7.76 (m, 3H), 8.03 (m, 3H).

EXAMPLE 19F Ethyl5-cyclopropyl-1-(2-ethylphenyl-)-1H-pyrazole-4-carboxylate

53% yield.

APCIMS 285 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.75 (m, 2H), 0.85 (m, 2H), 1.07 (m, 3H), 1.35(m, 3H), 1.78 (m, 1H), 2.36 (q, J=7.4, 2H), 4.27 (m, 2H), 7.23 (m, 2H),7.29-7.42 (m, 2H), 7.98 (s, 1H).

EXAMPLE 19G Ethyl5-cyclopropyl-1-(2-methylphenyl-)-1H-pyrazole-4-carboxylate

73% yield.

APCIMS 291 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.75-0.81 (m, 4H), 1.34 (dt, J=7, 0.8, 3H),1.83 (m, 1H), 2.05 (s, 3H), 4.28 (dq, J=7.2, 0.4, 2H), 7.30-7.38 (m,4H), 7.99 (s, 1H).

EXAMPLE 19H Ethyl5-cyclopropyl-1-(2-chlorophenyl-)-1H-pyrazole-4-carboxylate

75% yield.

APCIMS 291 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.6-0.9 (bs, 4H), 1.34 (dt, J=7.2, 3.6, 3H),1.85 (m, 1H), 4.28 (q, J=7.2, 2H), 7.37-7.44 (m, 3H), 7.52 (m, 1H), 8.03(s, 1H).

EXAMPLE 19I Ethyl5-cyclopropyl-1-(2-trifluoromethylphenyl-)-1H-pyrazole-4-carboxylate

69% yield.

APCIMS 341 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.62 (d, J=8.8, 2H), 0.78-0.85 (m, 2H), 1.35(t, J=7.2, 3H), 1.85 (m, 1H), 4.20 (dq, J=14.4, 7.2, 2H), 7.35-7.6 (m,4H), 8.03 (s, 1H).

EXAMPLE 19J Ethyl5-cyclopropyl-1-(2-fluorophenyl-)-1H-pyrazole-4-carboxylate

81% yield.

APCIMS 275 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.63 (m, 2H), 0.83 (m, 2H), 1.36 (t, J=7.2,3H), 1.92 (m, 1H), 4.20 (q, J=7.2, 2H), 7.21-7.29 (m, 2H), 7.43-7.48 (m,2H), 8.04 (s, 1H).

EXAMPLE 19K Ethyl5-cyclopropyl-1-(indazol-7-yl)-1H-pyrazole-4-carboxylate

59% yield.

APCIMS 297 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.56-0.60 (m, 2H), 1.00-1.23 (m, 2H), 1.37 (m,3H), 2.07 (m, 1H), 4.33 (dq, J=6.8, 1.6, 2H), 7.22 (m, 1H), 7.60 (d,J=6.8, 1H), 7.75 (d, J=7.6, 1H), 8.12 (s, 1H), 10.97 (bs, 1H).

EXAMPLE 19L Methyl5-ethyl-1-(benzothiazol-2-yl)-1H-pyrazole-4-carboxylate

69% yield.

APCIMS 288 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ1.34 (t, J=6.8, 3H), 3.69 (q, J=6.8, 2H), 3.85(s, 3H), 7.36 (t, J=7.6, 1H), 7.46 (t, J=7.2, 1H), 7.83 (d, J=8.0, 1H),7.91 (d, J=8.0, 1H), 8.01 (s, 1H).

EXAMPLE 19M Ethyl5-cyclopropyl-1-(2,4-dichloro-6-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate

43% yield.

APCIMS 393 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.78-0.85 (m, 2H), 0.85-0.91 (m, 2H), 1.37 (t,J=7.2, 3H), 1.70 (m, 1H), 4.30 (q, J=6.8, 2H), 7.3-7.7 (m, 2H), 8.08 (s,1H).

EXAMPLE 19N Ethyl5-cyclopropyl-1-(2-chloro-4-{methylsulfonyl}phenyl)-1H-pyrazole-4-carboxylate

70% yield.

APCIMS 369 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.68 (d, J=4.8, 2H), 0.82 (d, J=7.6, 2H), 1.37(t, J=7.2, 3H), 1.84 (m, 1H), 4.30 (q, J=7.2, 2H), 7.61 (d, J=8.4, 1H),7.96 (m, 1H), 8.04 (s, 1H), 8.12 (s, 1H).

EXAMPLE 19O Ethyl5-cyclopropyl-1-(2-chloro-4-{methylsulfonylmethylenesulfonyl}phenyl)-1H-pyrazole-4-carboxylate

61% yield.

APCIMS 447 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.65 (s, 2H), 0.84 (d, J=7.2, 2H), 1.35 (t,J=7.6, 3H), 1.84 (m, 1H), 3.29, (s, 3H), 4.30 (q, J=6.8, 2H), 4.62 (s,2H), 7.64 (d, J=7.6, 1H), 8.01 (dd, J=8.4, 2.0, 1H), 8.06 (s, 1H), 8.16(s, 1H).

EXAMPLE 19P Ethyl5-cyclopropyl-1-(2,5-dichlorophenyl)-1H-pyrazole-4-carboxylate

72% yield.

APCIMS 325 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.73 (s, 2H), 0.84 (d, J=6.8, 2H), 1.34 (t,J=7.2, 3H), 1.85 (m, 1H), 4.32 (q, J=7.2, 2H), 7.39-7.47 (m, 3H), 8.02(s, 1H).

EXAMPLE 19Q Ethyl5-cyclopropyl-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylate

72% yield.

APCIMS 325 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.73 (s, 2H), 0.84 (d, J=6.8, 2H), 1.34 (t,J=7.2, 3H), 1.85 (m, 1H), 4.32 (q, J=7.2, 2H), 7.39-7.47 (m, 3H), 8.02(s, 1H).

EXAMPLE 19R Ethyl5-cyclopropyl-1-(2,3-dichlorophenyl)-1H-pyrazole-4-carboxylate

74% yield.

APCIMS 325 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.67 (s, 2H), 0.78 (s, 2H), 1.34 (t, J=7.2,3H), 1.83 (m, 1H), 4.32 (m, 2H), 7.30-7.35 (m, 2H), 7.59 (m, 1H), 8.02(s, 1H).

EXAMPLE 19S Ethyl5-cyclopropyl-1-(2-chloro-5-methylsulfonylphenyl)-1H-pyrazole-4-carboxylate

38% yield.

APCIMS 369 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.70 (s, 2H), 0.82 (d, J=7.2, 2H), 1.35 (t,J=7.2, 3H), 1.83 (m, 1H), 3.08 (s, 3H), 4.33 (q, J=7.2, 2H), 7.75 (dd,J=6.4, 2.4, 1H), 7.98-8.04 (m, 2H), 8.05 (s, 1H).

EXAMPLE 19T Methyl5-ethyl-1-(benzimidazol-5-yl)-1H-pyrazole-4-carboxylate

56% yield.

APCIMS 271 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.98-1.16 (m, 3H), 2.81-3.07 (m, 2H), 3.76(s, 3H), 7.23 (d, J=8.4, 1H), 7.68 (bs, 2H), 7.96 (s, 1H), 8.38 (bs,1H), 12.75 (bs, 1H).

EXAMPLE 19U Ethyl5-cyclopropyl-1-(benzimidazol-5-yl)-1H-pyrazole-4-carboxylate

75% yield.

APCIMS 297 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.61 (dd, J=5.4, 1.4, 2H), 0.85-0.87 (m, 2H),1.37 (m, 3H), 1.98 (m, 1H), 4.31 (q, J=7.2, 2H), 7.44 (m, 1H), 7.76 (d,J=8.8. 1H), 7.85 (s, 1H), 8.01 (s, 1H), 8.37 (bs, 1H), 11.82 (bs, 1H).

EXAMPLE 19V Methyl5-ethyl-1-(3-chloroindazol-5-yl)-1H-pyrazole-4-carboxylate

63% yield.

APCIMS 305 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ1.16 (t, J=7.6, 3H), 2.96 (q, J=7.6, 2H), 3.88(s, 3H), 7.43-7.46 (m, 1H), 7.53 (d, J=8.8,1 H), 7.74(s, 1H), 8.06 (s,1H).

EXAMPLE 19W Methyl5-ethyl-1-(2-methylbenzimidazol-5-yl)-1H-pyrazole-4-carboxylate

65% yield.

APCIMS 284 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ1.11 (t, J=7.6, 3H), 2.62 (s, 3H), 2.93 (q,J=7.6, 2H), 7.18 (dd, J=8.4, 2.0, 1H), 7.54-7.56 (m, 2H), 8.01 (s, 1H).

EXAMPLE 19X Ethyl5-cyclopropyl-1-(2-chloro-5-hydroxysulfonylphenyl)-1H-pyrazole-4-carboxylate

82% yield.

APCIMS 369 [M−1]⁻

¹H NMR (CDCl₃) δ0.89-1.11 (m, 4H), 1.39 (t, J=7.2, 3H), 1.83 (q, J=7.0,1H), 4.35 (q, J=7.0, 2H), 6.92 (bs, 1H), 7.58 (d, J=8.4, 1H), 7.91-7.95(m, 2H), 8.44 (s, 1H).

EXAMPLE 19Y Ethyl5-cyclopropyl-1-(2-chloro-4-hydroxysulfonylphenyl)-1H-pyrazole-4-carboxylate

96% yield.

APCIMS 369 [M−1]⁻

¹H NMR (CDCl₃) δ0.85-0.91 (m, 4H), 1.37 (dt, J=7.0, 5.2, 3H), 1.75-1.87(m, 1H), 4.33 (q, J=7.0, 2H), 7.42 (d, J=8.0, 1H), 7.80 (d, J=8.0, 1H),8.02 (s, 1H), 8.16 (s, 1H).

EXAMPLE 19Z Ethyl 5-isopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylate

88% yield.

APCIMS 310 [M+1]⁺

¹H NMR (400, MHz, CDCl₃) δ8.95 (dd, J=4, 1.6, 1H), 8.26 (d, J=8, 1H),8.12 (s, 1H), 7.79 (t, J=8, 1H), 7.53 (m, 2H), 7.39 (dd, J=9, 4, 1H),4.32 (q, J=7, 2H), 3.01 (m, 1H), 1.38 (t, J=7, 3H), 1.21 (m, 6H).

EXAMPLE 19AA Ethyl 5-n-propyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylate

97% yield.

APCIMS 310 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ8.95 (d, J=4, 1H), 8.25 (d, J=9, 1H), 8.12 (s,1H), 7.79 (t, J=8, 1H), 7.56 (m, 2H), 7.38 (dd, J=8, 4, 1H), 4.32 (q,J=7, 2H), 2.71 (bs, 2H), 1.36 (m, 5H), 0.70 (t, J=7, 3H).

EXAMPLE 19BB Ethyl5-cyclopropyl-1-(2,1,3-benzothiazol-4-yl)-1H-pyrazole-4-carboxylate

67% yield.

APCIMS 315 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ8.11 (m, 2H), 7.70 (m, 2H), 4.31 (q, J=7, 2H),1.97 (m, 1H), 1.36 (t, J=7, 3H), 0.53-0.85 (m, 4H).

EXAMPLE 19CC Ethyl5-cyclopropyl-1-(2-aminosulfonylphenyl)-1H-pyrazole-4-carboxylate

72% yield.

APCIMS 336 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ8.17 (d, J=7, 1H), 8.04 (s, 1H), 7.69 (t, J=7,1H), 7.63 (t, J=7, 1H), 7.42 (d, J=7, 1H), 5.81 (s, 2H), 4.29 (q, J=7,2H), 1.80 (m, 1H), 1.34 (t, J=7, 3H), 0.4-1.0 (bs, 4H).

EXAMPLE 19DD Ethyl5-cyclopropyl-1-(2-methylthiophenyl)-1H-pyrazole-4-carboxylate

76% yield.

APCIMS 303 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ8.02 (s, 1H), 7.43 (m, 1H), 7.30 (d, J=8, 1H),7.23 (m, 2H), 4.27 (q, J=7, 2H), 2.36 (s, 3H), 1.86 (m, 1H), 1.34 (t,J=7, 3H), 0.75 (m, 4H).

EXAMPLE 19EE Methyl5-methoxymethyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylate

90% yield.

APCIMS 298 [M+1]⁺

¹H NMR (300 MHz, CDCl₃) δ8.99 (d, J=4, 1H), 8.30 (d, J=9, 1H), 8.20 (s,1H), 7.83 (t, J=8, 1H), 7.71 (m, 2H), 7.43 (dd, J=9,5, 1H), 4.56 (s,2H), 3.93 (s, 3H), 3.21 (s, 3H).

EXAMPLE 19FF Ethyl5-cyclopropyl-1-(isoquinolin-5-yl)-1H-pyrazole-4-carboxylate

69% yield.

APCIMS 308 [M+1]⁺

¹H NMR (CDCl₃) δ1.68-1.75 (m, 1H), 8.07 (s, 1H).

EXAMPLE 19GG Ethyl5-benzyloxymethyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate

93.5% yield.

APCIMS 388 [M+1]⁺

¹H NMR (CDCl₃) δ1.32-1.36 (s, 3H), 8.15 (s, 1H).

EXAMPLE 19HH Methyl5-ethyl-1-(benzotriazol-5-yl)-1H-pyrazole-4-carboxylate

95% yield

APCIMS 272 [M+1]⁺

¹H NMR (CDCl₃) δ1.12-1.16 (t,3H), 8.07 (s, 1H).

EXAMPLE 19II Methyl 5-ethyl-1-(indazol-6-yl)-1H-pyrazole-4-carboxylate

87% yield

APCIMS 270 [M+1]⁺

¹H NMR (CDCl₃) δ1.06-1.10 (t, 3H) ; 8.07 (s, 1H)

EXAMPLE 19JJ Methyl5-ethyl-1-(benzothiazol-6-yl)-1H-pyrazole-4-carboxylate

74% yield

APCIMS 288 [M+1]⁺

¹H NMR (CDCl₃) δ1.11-1.15 (t, 3H), 8.20 (s, 1H)

EXAMPLE 19LL Ethyl5-cyclobutyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate

93% yield

APCIMS 322 [M+1]⁺

¹H NMR (CDCl₃) δ3.44-3.53 (m, 1H), 8.08 (s, 1H)

EXAMPLE 19MM Ethyl5-cyclopropyl-1-(6-chloroquinolin-5-yl)-1H-pyrazole-4-carboxylate

23% yield

APCIMS 342 [M+1]⁺

¹H NMR (CDCl₃) δ1.70-1.80 (m, 1H), 8.04 (s, 1H)

EXAMPLE 19NN Methyl 5-ethyl-1-(indazol-5-yl)-1H-pyrazole-4-carboxylate

71.5% yield

APCIMS 271 [M+1]⁺

¹H NMR (CDCl₃) δ1.06-1.10 (t, 3H), 8.02 (s, 1H)

EXAMPLE 19OO Methyl5-ethyl-1-(1,4-benzodioxan-6-yl)-1H-pyrazole-4-carboxylate

85% yield

APCIMS 289 [M+1]⁺

¹H NMR (CDCl₃) δ1.12-1.16 (t, 3H), 7.96 (s, 1H)

EXAMPLE 19PP Ethyl5-isobutyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylate

98% yield

APCIMS 324 [M+1]⁺

¹H NMR (CDCl₃) δ2.68-2.70 (m, 1H), 8.14 (s, 1H)

EXAMPLE 19QQ Methyl5-ethyl-1-(1,3-benzodioxol-5-yl)-1H-pyrazole-4-carboxylate

76.6% yield

APCIMS 275 [M+1]⁺

¹H NMR (CDCl₃) δ1.10-1.14 (t, 3H), 7.94 (s, 1H)

EXAMPLE 19RR Ethyl5-cyclopropyl-1-(8-Bromoquinolin-5-yl)-1H-pyrazole-4-carboxylate

49% yield

APCIMS 388 [M+2]⁺

¹H NMR (CDCl₃) δ1.64-1.72 (m, 1H), 8.04 (s, 1H)

EXAMPLE 19SS Ethyl5-Cyclopropyl-1-(6-trifluoromethylquinolin-7-yl)-1H-pyrazole-4-carboxylate

65% yield

APCIMS 376 [M+1]⁺

¹H NMR (CDCl₃) δ1.81-1.88 (m, 1H), 8.12 (s, 1H)

EXAMPLE 19TT Ethyl 5-methyl-1-(6quinolinyl)-1H-pyrazole-4-carboxylate

40% yield.

¹H NMR (DMSO-d₆) d 1.26 (t, 3H); 2.57 (s, 3H); 4.22 (q, 2H); 7.6 (dd,1H); 7.89 (dd, 1H); 8.04 (s, 1H); 8.12-8.19 (m, 2H); 8.43 (d, 1H); 8.95(dd, 1H).

EXAMPLE 19UU Ethyl5-cyclopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylate

73.2% yield.

¹H NMR (DMSO-d₆) d 0.43 (dd, 2H); 0.83 (m, 2H); 1.29 (t, 3H); 2.18 (m,1H); 4.24 (q, 2H); 7.61 (dd, 1H); 7.98-8.04 (dd +s, 2H); 8.12 (d, 1H);8.26 (s, 1H); 8.46 (d, 1H); 8.96 (t, 1H);

EXAMPLE 19VV Ethyl5-methyl-1-(6-methoxy-5-quinolinyl)-1H-pyrazole-4-carboxylate

25% yield.

¹H NMR (DMSO-d₆) d 1.27 (t, 3H); 2.16 (s, 3H); 3.9 (s, 3H); 4.23 (q,2H); 7.34 (dd, 1H); 7.46 (m, 1H); 7.87 (d, 1H); 8.07 (s, 1H); 8.24 (d,1H); 8.8 (dd, 1H).

EXAMPLE 19WW Ethyl5-cyclopropyl-1-(6-methyl-5-quinolinyl)-1H-pyrazole-4-carboxylate

55.2% yield.

¹H NMR (DMSO-d₆) d 0.48-0.78 (m, 4H); 1.27 (t, 3H); 1.66 (m, 1H); 2.13,(s, 3H); 4.21 (q, 2H); 7.35 (dd, 1H); 7.5 (m, 1H); 7.8 (d, 1H); 8.11 (m,2H) 8.89 (t, 1H).

EXAMPLE 19XX Ethyl5-ethyl-1-(2-methyl-6-quinolinyl)-1H-pyrazole-4-carboxylate

36.1 % yield.

¹H NMR (DMSO-d₆) d 1.05 (t, 3H); 1.3 (t, 3H); 2.64 (s, 3H); 2.9 (q, 2H);4.2 (2q, 2H); 7.45 (d, 1H); 7.56 (d, 1H); 7.82 (m, 3H); 8.6 (d, 1H).

EXAMPLE 19YY Ethyl5ethyl-1-(6-methyl-5-quinolinyl)-1H-pyrazole-4-carboxylate

70.8 % yield.

¹H NMR (DMSO-d₆) d 0.83 (t, 3H); 1.33 (t, 3H); 2.15 (s, 3H); 2.50 (2q,2H); 4.31 (q, 2H); 7.33 (d, 1H); 7.53 (q, 1H); 7.87 (d, 1H); 8.19 (d+s,2H); 8.95 (d, 1H).

EXAMPLE 19ZZ Ethyl 5-ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylate

99.1 % yield.

¹H NMR (DMSO-d₆) d 1.04 (t, 3H); 1.26 (t, 3H); 2.94 (q, 2H); 4.23 (q,2H); 7.61 (q, 1H); 7.82 (dd, 1H); 8.03 (s, 1H); 8.15 (d, 2H); 8.47 (d,1H); 8.97 (d, 1H).

EXAMPLE 19AAA Methyl1-(2-quinoxalinyl)-5-ethyl-1H-pyrazole-4-carboxylate

77% yield

¹H NMR (400 MHz, DMSO-d₆) δ9.41 (s, 1H), 8.17 (s, 1H), 8.13 (dd, J=1.2,8, 1H), 8.01 (dd, J=1, 8, 1H), 7.87 (m, 2H), 3.78 (s, 3H), 3.40 (q, J=7,2H), 1.30 (t, J=7, 3H).

APCIMS 283 [M+1]⁺

EXAMPLE 19BBB Methyl1-(2-benzimidazyl)-5-ethyl-1H-pyrazole-4-carboxylate

61% yield.

¹H NMR (400 MHz, DMSO-d₆) δ13.14 (s, 1H), 8.19 (s, 1H), 7.63 (d, J=8,1H), 7.45 (d, J=8, 1H), 7.2 (m, 2H) 3.77 (s, 1H), 3.52 (q, J=7, 2H),1.22 (t, J=7, 3H).

APCIMS 271 [M+1]⁺

EXAMPLE 19CCC Methyl1-(2-trifluoromethyl-4-Chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

54% yield.

¹H NMR (400 MHz, DMSO-d₆) δ8.07 (d, J=2.4, 1H), 7.96 (d, J=3, 1H), 7.93(d, J=2, 1H), 7.76 (d, J=8, 1H), 4.19 (q, J=7, 2H), 1.76 (m, 1s), 1.24(t, J=7, 3H), 0.73 (d, J=8, 2H), 0.62 (d, J=4, 2H).

APCIMS 359 [M+1]⁺

EXAMPLE 19DDD Ethyl1-(2-fluoro-6-trifluoromethylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

70% yield.

¹H NMR (300 MHz, DMSO-d₆) δ8.08 (s, 1H), 7.97-7.87 (m, 3H), 4.24 (q,J=7, 2H), 1.74 (m, 1H), 1.30 (t, J=7, 3H), 0.86-0.68 (m, 4H).

APCIMS 343 [M+1]⁺

EXAMPLE 19EEE Ethyl1-(2-trifluoromethyl-4-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxlate

72% yield.

¹H NMR (400 MHz, DMSO-d₆) δ7.97 (s, 1H), 7.93 (dd, J=8, 3, 1H),7.84-7.73 (m, 2H), 4.21 (q, J=7, 2H), 1.77 (m, 1H), 1.26 (t, J=7, 3H),0.75-0.65 (m, 4H).

APCIMS 343 [M+1]⁺

EXAMPLE 19FFF Methyl 1-(2-quinolinyl)-5-ethyl-1H-pyrazole-4-carboxylate

82% yield

¹H NMR (300 MHz, DMSO-d₆) δ8.63 (d, J=9, 1H), 8.15 (s, 1H), 8.11-8.00(m, 3H), 7.86 (m, 1H), 7.69 (t, J=9, 1H), 3.82 (s, 3H), 3.50 (q, J=7,2H), 1.33 (t, J=7, 3H).

APCIMS 282 [M+1]⁺

EXAMPLE 19GGG Ethyl1-(2-chloro-5-hydroxycarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

89% yield

¹H NMR (300 MHz, DMSO-d₆) δ8.11 (dd, J=2.1, 8, 1H), 8.06 (d, J=1.8, 1H),8.040 (s, 1H), 7.88 (d, J=8, 1H), 4.25 (q, J=7, 2H), 1.87 (m, 1H), 1.30(t, J=7, 3H), 0.800-0.74 (m, 2H), 0.70-0.64 (m, 2H).

APCIMS 335 [M+1]⁺

EXAMPLE 19HHH Ethyl1-(4-benzimidazolyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

60% yield

¹H NMR (300 MHz, DMSO-d₆) δ8.28 (s, 1H), 8.01 (bs, 1H), 7.72 (bs, 1H),7.38-7.33 (m, 2H), 4.26 (q, J=7, 2H), 2.02 (m, 1H), 1.31 (t, J=7, 3H),0.56-0.48 (m, 4H).

APCIMS 297 [M+1]⁺

EXAMPLE 19III Ethyl1-(2-chloro-5-iodophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

79% yield

¹H NMR (300 MHz, CDCl₃) δ8.06 (s, 1H), 7.93 (d, J=1.5, 1H), 7.76 (dd,J=1.5, 8, 1H), 7.15 (d, J=8, 1H), 4.33 (q, J=7.2, 2H), 1.88 (m, 1H),1.39 (t, J=7.5, 3H), 0.91-0.76 (m, 4H).

APCIMS 417 [M+1]⁺

EXAMPLE 19JJJ Ethyl 1-phenyl-4-cyclopropyl-1H-pyrazole-3-carboxylate

76% yield

APCIMS 269 [M−1]⁻

¹H NMR (300 MHz, DMSO-d₆) δ8.92 (s, 1H), 7.87-7.84 (m, 2H), 7.49 (t,J=8, 2H), 7.33 (t, J=7.5, 1H), 4.28 (q, J=7, 2H); 2.54 (m, 1H), 1.32 (t,J=7, 3H), 1.00-0.91 (m, 4H).

EXAMPLE 19KKK Ethyl1-(2-chloro-5-methoxyphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

70% yield

APCIMS 321 [M+1]⁺

¹H NMR (300 MHz, CDCl₃) δ8.07 (s, 1H), 7.44 (d, J=9, 1H), 7.01 (m, 1H),6.69 (d, J=3, 1H), 4.34 (q, J=7, 2H), 1.94 (m, 1H), 1.40 (t, J=7, 3H),0.82 (bs, 4H).

EXAMPLE 19LLL Ethyl1-(1-isoquinolyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

15% yield

APCIMS 308 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ8.51 (d, J=6, 1H), 8.13 (d, J=8, 1, H), 8.08(d, 6, 1H), 8.07 (s, 1H), 7.85 (t, J=9, 1H), 7.67 (t, J=8, 1H), 7.44 (d,J=8, 1H), 4.23 (q, J=7, 2H), 1.96 (m, 1H), 1.27 (t, J=7, 3H), 0.62-0.56(m, 2H), 0.47-0.41 (m, 2H).

EXAMPLE 19MMM Methyl 5-butyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylate

93% yield.

APCIMS 310 [M+1]⁺

¹H NMR (300 MHz, CDCl₃) δ9.01 (m, 1H), 8.31 (d, J=8, 1H), 8.16 (s, 1H),7.85 (t, J=8, 1H), 7.61 (m, 2H), 7.44 (dd, J=9, 4, 1H), 3.91 (s, 3H),2.79 (bs, 2H), 1.37 (quintet, J=8, 2H), 1.15 (quintet, 2H), 0.69 (t,J=7, 3H).

EXAMPLE 19NNN Ethyl5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylate

81.1% yield.

¹H NMR (DMSO-d₆) d 1.27 (d+t, 9H); 3.17 (m, 1H); 4.23 (q, 2H); 7.63 (q,1H); 7.75 (dd, 1H); 8.01 (s, 1H); 8.11 (d, 1H); 8.15 (d, 1H); 8.48 (dd,1H); 8.98 (q, 1H).

EXAMPLE 19OOO Ethyl 5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylate

91.5% yield.

¹H NMR (DMSO-d₆) d 0.69 (t, 3H); 1.26 (t, 3H); 1.42 (q, 2H); 2.93 (t,2H); 4.22 (q, 2H); 7.61 (q, 1H); 7.82 (dd, 1H); 8.04 (s, 1H); 8.16 (d+s,2H); 8.47 (d, 1H); 8.98 (q, 1H).

The title compounds of Examples 20A-20G were prepared using proceduresanalogous to that described in Bajnati, A.; Hubert-Habart, M. Bull. Soc.Chim. Fr. 1988, 540, and Example 12A.

EXAMPLE 20A n-Butyl1-(2,3-dimethoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate

33% yield

¹H NMR (400 MHz, CDCl₃) δ0.93 (m, 3H), 1.43 (m, 2H), 1.68 (t, J=6.8,2H), 2.58 (s, 3H), 3.68 (s, 3H), 3.89 (s, 3H), 4.23 (m, 2H), 6.87 (m,1H), 7.11 (m, 1H), 7.23 (s, 1H), 7.28 (m, 1H), 8.45 (s, 1H).

APCIMS 319 [M+1]⁺

EXAMPLE 20B n-Butyl1-(naphthalen-2-yl)-3-methyl-1H-pyrazole-4-carboxylate

24% yield

¹H NMR (400 MHz, CDCl₃) δ0.96 (m, 3H), 1.46 (m, 2H), 1.72 (m, 2H),2.57(s, 3H), 4.26 (m, 2H), 7.49 (m, 2H), 7.78-7.94 (m, 4H), 8.10 (s,1H), 8.44 (s, 1H).

APCIMS 309[M+1]⁺

EXAMPLE 20C n-Butyl 1-(o-biphenyl)-3-methyl-1H-pyrazole-4-carboxylate

75% yield

¹H NMR (400 MHz, CDCl₃) δ0.88 (t, J=7.6, 3H), 1.33 (m, 2H), 1.56 (m,2H), 2.47(s, 3H), 4.10 (m, 2H), 7.10 (m, 2H), 7.26 (m, 3H), 7.42 (m,4H), 7.57 (m, 1H).

APCIMS 335 [M+1]⁺

EXAMPLE 20D n-Butyl 1-phenyl-3-ethyl-1H-pyrazole-4-carboxylate

36% yield

¹H NMR (400 MHz, CDCl₃) δ0.95 (t, J=7.8, 3H), 1.29 (t, J=7.6, 3H), 1.43(m, 2H), 1.68 (m, 2H), 2.95 (q, J=7.6, 2H), 4.24 (t, J=6.4, 2H), 7.27(m, 1H), 7.42 (m, 2H), 7.65 (m, 2H), 8.31 (s, 1H).

APCIMS 273 [M+1]⁺

EXAMPLE 20E n-Butyl1-(2,1,3-benzothiadiazol4-yl)-3-methyl-1H-pyrazole-4-carboxylate

25% yield

¹H NMR (400 MHz, CDCl₃) δ0.97 (t, J=7.2, 3H), 1.46 (m, 2H), 1.74 (m,2H), 2.58 (s, 3H), 4.28 (t, J=6.8, 2H), 7.68 (t, J=8.6, 1H), 7.92 (d,J=8.8, 1H) 8.21 (d, J=7.2, 1H), 9.53 (s, 1H).

APCIMS 217 [M+1]⁺

EXAMPLE 20F n-Butyl 1-(indazol-7-yl)-3-methyl-1H-pyrazole-4-carboxylate

35% yield

¹H NMR (400 MHz, DMSO-d₆) δ0.90 (t, J=7.4, 3H), 1.40 (m, 2H), 1.64 (m,2H), 2.83 (s, 3H), 4.19 (t, J=6.4, 2H), 7.17 (t, J=7.6, 1H), 7.72 (d,J=7.6, 1H), 8.18 (s, 1H), 9.03 (s, 1H), 13.13 (bs, 1H).

APCIMS 299 [M+1]⁺

EXAMPLE 20G n-Butyl 1-benzyl-3-methyl-1H-pyrazole-4-carboxylate

68% yield

¹H NMR (400 MHz, CDCl₃) δ0.93 (t, J=7.2, 3H), 1.40 (m, 2H), 1.66 (m,2H), 2.45 (s, 3H), 4.19 (t, J=6.6, 2H), 5.2 (s, 2H), 7.20-7.24 (m, 2H),7.32-7.36 (m, 3H), 7.77 (s, 1H).

APCIMS 273 [M+1]⁺

EXAMPLE 21 Ethyl5-cyclopropyl-1-(2-pyrrol-1-ylphenyl-)-1H-pyrazole-4-carboxylate

A mixture of ethyl5-cyclopropyl-1-(2-nitrophenyl-)-1H-pyrazole-4-carboxylate (2.5 g, 8.3mmol) and Pd/C (10%, 0.550 g, 20% w/w) in ethyl acetate (60 mL) wasshaken under a H₂ atmosphere (50 psig) for 3 h. The resulting mixturewas filtered through Celite® and concentrated in vacuo to afford 2.52 gof a reddish oil.

A portion of the residue (458.5 mg, 1.69 mmol) and2,5-dimethoxytetrahydrofuran (0.328 mL, 2.53 mmol) in glacial aceticacid (6 mL) was heated to 110° C. under a N₂ atmosphere for 1 h. Thereaction mixture was cooled to 23° C. and concentrated in vacuo. Theresidue was dissolved in ethyl acetate, washed twice with NaHCO₃ (sat aqsol) and brine, dried over MgSO₄, and filtered. The filtrate was passedover a short column of silica gel. The eluate was concentrated in vacuoto yield 0.4965 g (91%) of the title compound as a dark oil.

APCIMS 322 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.35-0.80 (m, 4H), 1.01 (m, 1H), 1.36 (t,J=9.4, 3H), 4.30 (q, J=8.8, 2H), 7.42-7.61 (m, 4H), 8.08 (s, 1H).

EXAMPLE 22A Ethyl5-cyclopropyl-1-(2-chloro-5-{dimethylaminosulfonyl}phenyl)-1H-pyrazole-4-carboxylate

A mixture of ethyl5-cyclopropyl-1-(2-chloro-5-{hydroxysulfonyl}phenyl)-1H-pyrazole-4-carboxylate(1.48 g, 4.0 mmol) and PCl₅ (1.79 g, 8.6 mmol) in POCl₃ (6 mL) under anitrogen atmosphere was heated at 95° C. for 30 min, cooled to 23° C.and poured slowly over ice. The resulting mixture was extracted withEtOAc. The organic layer was washed three times with cold water, brine,dried over MgSO₄, filtered and concentrated in vacuo to afford 1.48 g(95% yield) of ethyl5-cyclopropyl-1-(2-chloro-5-{chlorosulfonyl}phenyl)-1H-pyrazole-4-carboxylateas a yellow oil.

A solution of ethyl5-cyclopropyl-1-(2-chloro-5-{chlorosulfonyl}phenyl)-1H-pyrazole-4-carboxylate(0.315 g, 0.812 mmol) in CH₂Cl₂ (3 mL) was treated at 23° C. withdimethylamine (2 M in THF, 3 mL, 6 mmol). The resulting mixture wasstirred for 15 min and concentrated in vacuo. The residue waspartitioned between EtOAc and HCl (0.1 M aq). The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by Flash 40S™ chromatography (65:35hexanes-EtOAc) to afford 0.276 g (86% yield) of desired product as acolorless oil.

APCIMS 397 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.68 (d, J=5.6, 2H), 0.81 (d, J=8.4, 2H), 1.35(t, J=7.2, 3H), 1.83 (m, 1H), 2.74, (s, 6H), 4.30 (q, J=7.2, 2H),7.70-7.25 (m, 1H), 7.80-7.83 (m, 2H), 8.04 (s, 1H).

The title compounds of Examples 22-22E were prepared using proceduresanalogous to that used for Example 22A.

EXAMPLE 22B Ethyl5-cyclopropyl-1-(2-chloro-5-{aminosulfonyl}phenyl)-1H-pyrazole-4-carboxylate

58% yield.

APCIMS 368 [M−1]⁻

¹H NMR (400 MHz, CDCl₃) δ0.73 (s, 2H), 0.84 (d, J=5.6, 2H), 1.37 (t,J=7.2, 3H), 1.85 (m, 1H), 4.31 (q, J=7.2, 2H), 7.69 (d, J=7.2, 1H), 7.96(m, 2H), 8.06 (s, 1H).

EXAMPLE 22C Ethyl5-cyclopropyl-1-(2-chloro-5-{methylaminosulfonyl}phenyl)-1H-pyrazole-4-carboxylate

97% yield.

APCIMS 368 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.72 (s, 2H), 0.86 (d, J=8, 2H), 1.37 (t,J=7.2, 3H), 1.85 (m, 1H), 2.70 (s, 3H), 4.32 (q, J=7.2, 2H), 7.71 (d,J=9.2, 1H), 7.90-7.93 (m, 2H), 8.06 (s, 1H).

EXAMPLE 22D Ethyl5-cyclopropyl-1-(2-chloro-4-{dimethylaminosulfonyl}phenyl)-1H-pyrazole-4-carboxylate

100% yield.

APCIMS 397 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.67 (bs, 2H), 0.82 (d, J=6.4, 2H), 1.35 (t,J=7.2, 3H), 1.85 (m, 1H), 2.76, (s, 6H), 4.32 (q, J=7.2, 2H), 7.57 (d,J=8.4, 1H), 7.78 (dd, J=8.4, 2.0, 1H), 7.94 (s, 1H), 8.05 (s, 1H).

EXAMPLE 22E Ethyl5-cyclopropyl-1-(2-chloro-4-{methylaminosulfonyl}phenyl)-1H-pyrazole-4-carboxylate

93% yield.

APCIMS 384 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.58-0.61 (m, 2H), 0.73-0.78 (m, 2H), 1.35(t, J=6.8, 3H), 1.85 (m, 1H), 2.47, (s, 6H), 4.21 (q, J=7.2, 2H), 7.77(dd, J=9.6, 4.8, 1H), 7.88 (s, 1H), 8.03 (d, J=3.5, 1H).

The title compounds of Examples 23A-23B were prepared using proceduresanalogous to that described in Kikugawa, Y. Synthesis, 1981, 124.

EXAMPLE 23A Methyl1-(1-methylbenzimidaz-2-yl)-5-ethyl-1H-pyrazole-4-carboxylate

61% yield

¹H NMR (300 MHz, DMSO-d₆) δ8.23 (s, 1H), 7.78-7.69 (m, 2H), 7.45-7.32(m, 2H), 8.83 (s, 3H), 3.72 (s, 3H), 3.04 (q, J=7, 2H), 1.14 (t, J=7,3H).

APCIMS 285 [M+1]⁺

EXAMPLE 23B Methyl5-ethyl-1-(1-methylbenzimidazol-6-yl)-1H-pyrazole-4-carboxylate

35% yield.

APCIMS 284 [M+1]⁺

¹H NMR (300 MHz, CDCl₃) δ1.03 (t, J=7.35, 3H), 2.87 (q, J=7.35, 2H),3.80 (s, 3H), 3.88 (s, 3H), 7.26-7.30 (m, 1H), 7.78-7.81 (m, 2H), 8.02(s, 1H), 8.36 (s, 1H).

EXAMPLE 24 Ethyl5-cyclopropyl-1-(2-methylsulfonylphenyl)-1H-pyrazole-4-carboxylate

A solution of ethyl5-cyclopropyl-1-(2-methylthiophenyl)-1H-pyrazole-4-carboxylate (0.456 g,1.51 mmol) in methanol (6 mL) at 0° C. was treated with a solution ofoxone (1.40 g, 2.27 mmol) in water (6 mL). The resulting slurry was wasstirred at 23° C. for 8 h. The mixture was treated with additional oxone(0.46 g, 0.76 mmol), stirred for 14 h and partitioned between CH₂Cl₂ andwater. The organic layer was washed with water, dried over MgSO₄ andconcentrated in vacuo to afford 0.504 g (100%) of the title compound.

APCIMS 335 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ8.23 (dd, J=8, 2, 1H), 8.03 (s, 1H), 7.77 (t,J=8, 1H), 7.71 (t, J=8, 1H), 4.43 (d, J=7, 1H), 4.30 (q, J=7, 2H), 3.27(s, 3H), 1.81 (m, 1H), 1.36 (t, J=7, 3H), 0.4-1.0 (bs, 4H).

EXAMPLE 25 Ethyl5-cyclopropyl-1-(2-methylaminosulfonylphenyl)-1H-pyrazole-4-carboxylateand (Example 25A) Ethyl5-cyclopropyl-1-(2-dimethylaminosulfonylphenyl)-1H-pyrazole-4-carboxylate(Example 25B)

A solution of ethyl5-cyclopropyl-1-(2-aminosulfonylphenyl)-1H-pyrazole-4-carboxylate (0.503g, 1.50 mmol) in dry DMSO (5 mL) at 23° C. was treated with NaH (60% inmineral oil, 0.090 g, 2.25 mmol) and stirred for 1.5 h. The resultingmixture was treated with dimethylsulfate (0.213 mL, 2.25 mmol), stirredfor 20 h and partitioned between EtOAc and water. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified by Flash 40M™ chromatography (hexanes-EtOAc 60:40 to 50:50) toprovide 0.141 g (27%) of Example 25A and and 0.231 g (42%) of Example25B.

EXAMPLE 25A Ethyl5-cyclopropyl-1-(2-methylaminosulfonylphenyl)-1H-pyrazole-4-carboxylate

APCIMS 350 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ8.13 (dd, J=8, 1.4, 1H), 8.04 (s, 1H), 7.71 (t,J=8, 1.6, 1H), 7.65 (t, J=8, 1.6, 1H), 7.44 (dd, 8, 1.2, 1H), 5.93 (q,J=5, 1H), 4.31 (q, J=7, 2H), 2.65 (d, J=5, 3H), 1.82 (m, 1H), 1.36 (t,J=7, 3H), 0.4-1.1 (m, 4H).

EXAMPLE 25B Ethyl5-cyclopropyl-1-(2-dimethylaminosulfonylphenyl)-1H-pyrazole-4-carboxylate

APCIMS 364 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ8.07 (dd, J=7, 2, 1H), 8.00 (s, 1H), 7.68 (m,2H), 7.35 (dd, J=7, 2, 1H), 4.29 (q, J=7, 2H), 2.67 (s, 6H), 1.88 (m,1H), 1.36 (t, J=7, 3H), 0.64-0.93 (m, 4H).

EXAMPLE 26A Ethyl1-(2-chloro-5-methylaminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

A solution of ethyl1-(2-chloro-5-hydroxycarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate(1.32 g, 3.73 mmol) in thionyl chloride (7.5 mL) was heated at refluxfor 2 h under a nitrogen atmosphere. The resulting solution wasconcentrated in vacuo. A solution of the residue in anhydrous CH₂Cl₂ (10mL) under a nitrogen atmosphere was treated with methylamine (2 Msolution in THF, 9.33 mL, 18.7 mmol) followed by a catalytic amount of4-dimethylaminopyridine. The resulting mixture was stirred for 6 h andpartitioned between ethyl acetate and HCl (1 M aq). The organic layerwas washed with brine, NaHCO₃ (sat aq sol), and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified by flash40M™ chromatography (75:25 ethyl acetate/hexanes) to afford 1.00 g (77%yield) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ8.08 (s, 1H), 7.88 (dd, J=2, 8, 1H), 7.81 (d,J=2, 1H), 7.63 (d, J=9, 1H), 6.40 (bs, 1H), 4.33 (q, J=7, 2H), 3.02 (d,J=4, 3H), 1.89 m, 1H), 1.40 (t, J=7, 3H), 0.92-0.75 (m, 4H).

APCIMS 348 [M+1]⁺

The title compounds of Examples 26B-26C were prepared using proceduresanalogous to that used for Example 26A.

EXAMPLE 26B Ethyl1-(2-chloro-5-dimethylaminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

45% yield

¹H NMR (300 MHz, CDCl₃) δ8.07 (s, 1H), 7.59 (d, J=6, 1H), 7.52 (dd, J=2,6, 1H), 7.48 (d, J=2, 1H), 4.33 (q, J=7, 2H), 3.12 (bs, 3H), 3.05 (bs,3H), 1.88 (m, 1H), 1.39 (t, J=7, 3H), 0.94-0.80 (m, 4H).

APCIMS 362 [M+1]⁺

EXAMPLE 26C Ethyl1-(2-chloro-5-aminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylate

27% yield

¹H NMR (300 MHz, CDCl₃) δ8.17 (s, 1H), 8.10-8.07 (m, 2H), 8.05 (s, 1H),7.85 (d, J=9, 1H), 7.67 (s, 1H), 4.25 (q, J=7, 2H), 1.88 (m, 1H), 1.30(t, J=7, 3H), 0.81-0.74 (m, 2H), 0.70-0.63 (m, 2H).

APCIMS 334 [M+1]⁺

The title compound of Example 27 was prepared using a procedureanalogous to that used for Example 13A.

EXAMPLE 27 5-Ethyl-1-(benzothiazol-6-yl)-1H-pyrazole-4-carboxylic acid

78% yield.

APCIMS 272 [M−1]⁻

¹H NMR (DMSO-d₈) δ0.96-1.02 (t, 3H); 7.81 (s, 1H)

The title compounds of Examples 28A-28RRR were prepared using aprocedure analogous to that used for Example 14A.

EXAMPLE 28A5-Cyclopropyl-1-(2,3-dimethoxyphenyl)-1H-pyrazole-4-carboxylic acid

83% yield

¹H NMR (400 MHz, DMSO-d6) δ0.68 (d, J=8.4, 4H), 1.83 (m, 1H), 3.54 (s,3H), 3.85 (s, 3H), 6.94 (d, J=7.6, 1H), 7.19 (m, 2H), 7.87 (s, 1H),12.26 (s, 1H).

APCIMS 287 [M−1]⁻

EXAMPLE 28B 3-Methyl-1-(2,3-dimethoxyphenyl)-1H-pyrazole-4-carboxylicacid

81% yield

¹H NMR (400 MHz, DMSO-d₆) δ2.38 (s, 3H), 3.64 (s, 3H), 3.84 (s, 3H),7.14 (m, 3H), 8.41 (s, 1H), 12.41 (s, 1H).

APCIMS 261 [M−1]⁻

EXAMPLE 28C

5-Cyclopropyl-1-(naphthalen-1-yl)-1H-pyrazole-4-carboxylic acid

87% yield

¹H NMR (400 MHz, DMSO-d₆) δ0.56 (d, J=7.2, 4H), 1.82 (m, 1H), 7.12 (d,J=7.6, 1H), 7.58 (m, 4H), 8.10 (m, 3H), 12.38 (s, 1H).

APCIMS 279 [M+1]⁺

EXAMPLE 28D 5-Cyclopropyl-1-(naphthalen-2-yl)-1H-pyrazole-4-carboxylicacid

91% yield

¹H NMR (400 MHz, DMSO-d₆) δ0.48 (m, 2H), 0.80 (m, 2H), 2.15 (m, 1H),7.58 (m, 2H), 7.71 (m, 1H), 8.01 (m, 4H), 8.16 (s, 1H), 12.35 (s, 1H).

APCIMS 277 [M−1]⁻

EXAMPLE 28E 3-Methyl-1-(naphthalen-2-yl)-1H-pyrazole-4-carboxylic acid

91% yield

¹H NMR (400 MHz, DMSO-d₆) δ2.50 (s, 3H), 7.57 (m, 2H), 8.06 (m, 4H),8.43 (s, 1H), 9.04(s, 1H).

APCIMS 251 [M−1]⁻

EXAMPLE 28F 3-Methyl-1-(2-biphenyl)-1H-pyrazole-4-carboxylic acid

87% yield

¹H NMR (400 MHz, DMSO-d₆) δ2.28 (s, 3H), 7.05 (m, 2H), 7.27 (m, 3H),7.45-7.54 (m, 4H), 7.72 (s, 1H).

APCIMS 277 [M−1]⁻

EXAMPLE 28G 5-Cyclopropyl-1-(o-biphenyl)-1H-pyrazole-4-carboxylic acid

75% yield

¹H NMR (400 MHz, DMSO-d₆) δ0.44 (m, 4H), 1.04 (m, 1H), 6.98 (m, 2H),7.25 (m, 3H), 7.44-7.62 (m, 4H), 7.85 (s, 1H), 12.14 (s, 1H).

APCIMS 303 [M−1]⁻

EXAMPLE 28H 3-Ethyl-1-phenyl-1H-pyrazole-4-carboxylic acid

88% yield

¹H NMR (400 MHz, DMSO-d₆) δ1.18 (t, J=6.3, 3H), 2.82 (q, J=7.2, 2H),7.28 (t, J=7.2, 1H), 7.44 (m, 2H), 7.84 (m, 2H), 8.84 (s, 1H), 12.43 (s,1H).

APCIMS 215 [M−1]⁻

EXAMPLE 28I 5-Cyclopropyl-1-(2-nitrophenyl)-1H-pyrazole-4-carboxylicacid

89% yield

¹H NMR (400 MHz, DMSO-d₆) δ0.58 (m, 2H), 0.77 (m, 2H), 1.94 (m, 1H),7.79 (m, 1H), 7.91 (m, 2H), 8.13 (d, J=7.6, 1H), 12.48 (s, 1H).

APCIMS 273[M−1]⁻

EXAMPLE 28J5-Cyclopropyl-1-(2-pyrrol-1-ylphenyl)-1H-pyrazole-4-carboxylic acid

95% yield

¹H NMR (400 MHz, DMSO-d₆) δ0.41-0.62 (m, 4H), 1.04 (m, 1H), 6.13 (m,2H), 6.52 (m, 2H), 7.50-7.71 (m, 4H), 7.98 (s, 1H).

APCIMS 292[M−1]⁻

EXAMPLE 28K 5-Cyclopropyl-1-(2-ethylphenyl)-1H-pyrazole-4-carboxylicacid

73% yield

¹H NMR (400 MHz, CDCl₃) δ0.78 (dd, J=8.4, 1.6, 2H), 0.88 (m, 2H), 1.09(dt, J=7.6, 1.2, 3H), 1.84 (m, 1H), 2.37 (q, J=7.6, 2H), 7.24 (m, 2H),7.40 (m, 2H), 8.07 (s, 1H).

APCIMS 255 [M−1]⁻

EXAMPLE 28L 5-Cyclopropyl-1-(2-methylphenyl)-1H-pyrazole-4-carboxylicacid

¹H NMR (400 MHz, CDCl₃) δ0.8-0.89 (m, 4H), 1.87 (m, 1H), 2.09 (s, 3H),7.2-7.5 (m, 4H), 8.10 (s, 1H).

APCIMS 241 [M−1]⁻

EXAMPLE 28M 5-Cyclopropyl-1-(2-chlorophenyl)-1H-pyrazole-4-carboxylicacid

55% yield.

APCIMS 261 [M+1]⁺

¹H NMR (400 MHz, CDCl₃) δ0.84 (bs, 4H), 1.95 (m, 1H), 7.41-7.52 (m, 3H),7.58 (dd, J=9.4, 2.2, 1H), 8.15 (s, 1H).

EXAMPLE 28N5-Cyclopropyl-1-(2-trifluoromethoxyphenyl)-1H-pyrazole-4-carboxylic acid

100% yield.

APCIMS 311 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.56 (d, J=5.6, 2H), 0.71 (dd, J=8.4, 4.4,2H), 1.78 (m, 1H), 7.5-7.7 (m, 4H), 7.93 (s, 1H), 12.38 (s, 1H).

EXAMPLE 28O 5-Cyclopropyl-1-(2-fluorophenyl)-1H-pyrazole-4-carboxylicacid

84% yield.

APCIMS 245 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.56 (m, 2H), 0.72 (m, 2H), 1.85 (m, 1H),7.35 (m, 1H), 7.45 (m, 1H), 7.58 (m, 2H), 7.92 (s, 1H).

EXAMPLE 28P3-Methyl-1-(2,1,3-benzothiadiazol-4-yl)-1H-pyrazole-4-carboxylic acid

79% yield.

APCIMS 259 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ2.47 (s, 3H), 7.82 (m, 1H), 8.05 (dd, J=8.4,2.8, 1H), 8.15 (dd, J=7.6, 2.8, 1H), 9.41 (s, 1H), 12.63 (s, 1H).

EXAMPLE 28Q 5-Cyclopropyl-1-(indazol-7-yl)-1H-pyrazole-4-carboxylic acid

78% yield.

APCIMS 267 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.47-0.51 (m, 2H), 0.61-0.66 (m, 2H), 1.96(m, 1H), 7.20 (t, J=7.6, 1H), 7.45 (d, J=7.6, 1H), 7.87 (d, J=8.0, 1H),7.99 (s, 1H), 8.19 (s, 1H).

EXAMPLE 28R 3-Methyl-1-(indazol-7-yl)-1H-pyrazole-4-carboxylic acid

79% yield.

APCIMS 241 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ2.51 (s, 3H), 7.17 (t, J=8.0, 1H), 7.73 (d,J=8.0, 1H), 7.81 (d, J=7.6, 1H), 8.22 (s, 1H), 9.03 (bs, 1H).

EXAMPLE 28S 5-Ethyl-1-(benzothiazol-2-yl)-1H-pyrazole-4-carboxylic acid

84% yield.

APCIMS 272 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ1.25 (t, J=6.8, 3H), 3.61 (q, J=6.8, 2H),7.41-7.53 (m, 2H), 7.92 (d, J=8.4, 1H), 8.08 (s, 1H).

EXAMPLE 28T5-Cyclopropyl-1-(2-chloro-4-{methylsulfonyl}phenyl)-1H-pyrazole-4-carboxylicacid

98% yield.

APCIMS 339 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.68-0.70 (m, 2H), 0.76-0.79 (m, 2H), 1.87(m, 1H), 3.34 (s, 3H), 7.95-8.10 (m, 3H), 8.29 (s, 1H).

EXAMPLE 28U5-Cyclopropyl-1-(2-chloro-4-{methylsulfonylmethylenesulfonyl}phenyl)-1H-pyrazole-4-carboxylicacid

78% yield.

APCIMS 417 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.63 (m, 2H), 0.73-0.79 (m, 2H), 1.88 (m,1H), 3.27(s, 3H), 7.99-8.16 (m, 3H), 8.30 (s, 1H).

EXAMPLE 28V5-Cyclopropyl-1-(2-chloro-5-{dimethylaminosulfonyl}phenyl)-1H-pyrazole-4-carboxylicacid

82% yield.

APCIMS 368 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.61 (d, J=2.0, 2H), 0.72 (d, J=7.6, 2H),1.86 (m, 1H), 2.63 (s, 6H), 7.92-8.01 (m, 3H), 12.44 (s, 1H).

EXAMPLE 28W5-Cyclopropyl-1-(2-chloro-5-{aminosulfonyl}phenyl)-1H-pyrazole-4-carboxylicacid

82% yield.

APCIMS 368 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.65 (s, 2H), 0.75 (d, J=8.0, 2H), 1.84 (m,1H), 7.61 (s, 1H), 7.92-7.98 (m, 2H), 12.47 (s, 1H).

EXAMPLE 28X5-Cyclopropyl-1-(2-chloro-5-{methylaminosulfonyl}phenyl)-1H-pyrazole-4-carboxylicacid

75% yield.

APCIMS 354 [M−1]⁻

¹H NMR (400 MHz, DMSO-d6) δ0.62 (s, 2H), 0.73 (d, J=8.0, 2H), 1.86 (m,1H), 2.43 (d, J=2.8, 3H), 7.67 (d, J=4.8, 1H, 7.92-7.98 (m, 3H), 12.47(s, 1H).

EXAMPLE 28Y5-Cyclopropyl-1-(2,5-dichlorophenyl)-1H-pyrazole-4-carboxylic acid

97% yield.

APCIMS 295 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.62-0.64 (m, 2H), 0.70-0.74 (m, 2H), 1.82(m, 1H), 7.65 (dd, J=8.8, 2.4, 1H), 7.72 (d, J=8.4, 1H), 7.85 (d, J=2.4,1H), 7.93 (s, 1H).

EXAMPLE 28Z5-Cyclopropyl-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid

94% yield.

APCIMS 295 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.64-0.65 (m, 2H), 0.71-0.74 (m, 2H), 1.83(m, 1H), 7.60-7.68 (m, 3H), 7.92 (s, 1H), 12.41 (s, 1H).

EXAMPLE 28AA5-Cyclopropyl-1-(2,3-dichlorophenyl)-1H-pyrazole-4-carboxylic acid

91% yield.

APCIMS 295 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.65 (s, 2H), 0.73 (s, 2H), 1.83 (m, 1H),7.53 (t, J=8.0, 1H), 7.63 (dd, J=8.0, 1.6, 1H), 7.86 (dd, J=8.0, 1.2,1H), 7.96 (s, 1H), 12.41 (s, 1H).

EXAMPLE 28BB5-Cyclopropyl-1-(2-chloro-5-methylsulfonylphenyl)-1H-pyrazole-4-carboxylicacid

77% yield.

APCIMS 339 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.61-0.63 (m, 2H), 0.71 (d, J=6.8, 2H), 1.83(m, 1H), 3.29 (s, 3H), 7.97-8.09 (m, 3H), 8.18 (s, 1H), 12.44 (s, 1H).

EXAMPLE 28CC 5-Ethyl-1-(benzimidazol-5-yl)-1H-pyrazole-4-carboxylic acid

82% yield.

APCIMS 255 [M−1]⁻

¹H INMR (400 MHz, DMSO-d₆) δ0.97 (t, J=7.2, 3H), 2.84 (q, J=7.2, 2H),7.21 (d, J=8.4, 1H), 7.65-7.69 (m, 2H), 7.88 (s, 1H), 8.33 (s, 1H).

EXAMPLE 28DD5-Cyclopropyl-1-(2-chloro-4-{dimethylaminosulfonyl}phenyl)-1H-pyrazole-4-carboxylicacid

92% yield.

APCIMS 368 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.60-0.63 (m, 2H), 0.80-0.82 (m, 2H), 1.80(m, 1H), 2.68(s, 6H), 7.70 (s, 1H), 7.78-7.97 (m, 2H), 7.97 (s, 1H).

EXAMPLE 28EE5-Cyclopropyl-1-(2-chloro-4-{methylaminosulfonyl}phenyl)-1H-pyrazole-4-carboxylicacid

84% yield.

APCIMS 354 [M−1]⁻

¹H NMR (400 MHz, DMSO-d6) δ0.63 (d, J=4.8, 2H), 0.73 (d, J=8.4, 2H),1.84 (m, 1H), 2.47(s, 3H), 7.76 (t, J=4.6, 1H), 7.88 (s, 1H), 8.00 (d,J=15.2, 1H), 12.42 (s, 1H).

EXAMPLE 28FF5-Cyclopropyl-1-(benzimidazol-5-yl)-1H-pyrazole-4-carboxylic acid

59% yield.

APCIMS 267 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.50-0.54 (m, 2H), 0.71-0.76 (m, 2H), 2.05(m, 1H), 7.33 (dd, J=9.4, 1.8, 1H), 7.66 (d, J=8.4, 1H), 7.73 (s, 1H),7.89 (s, 1H), 8.32 (s, 1 H), 12.25 (s, 1H) 12.69 (bs, 1H).

EXAMPLE 28GG 3-Methyl-1-benzyl-1H-pyrazole-4-carboxylic acid

96% yield.

APCIMS 215 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ2.29 (s, 3H), 5.26 (s, 2H), 7.25-7.38 (m,5H), 8.27 (s, 1H), 12.18 (bs, 1H).

EXAMPLE 28HH 5-Ethyl-1-(3-chloroindazol-5-yl)-1H-pyrazole-4-carboxylicacid

85% yield.

APCIMS 289 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.97 (t, J=7.2, 3H), 2.83 (q, J=7.2, 2H),7.48 (dd, J=8.8, 1.6, 1H), 7.69-7.75 (m, 2H), 7.92 (s, 1H), 12.41 (s,1H), 13.60 (s, 1H).

EXAMPLE 28II 5-Ethyl-1-(1-methylbenzimidazol-6-yl)-1H-pyrazole-4-carboxylic acid

76% yield.

APCIMS 269 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.97 (t, J=7.6, 3H), 2.86 (q, J=7.2, 2H),3.90 (s, 3H), 7.38 (dd, J=8.6, 2.2, 1H), 7.81-7.93 (m, 3H), 8.75 (s,1H).

EXAMPLE 28JJ 5-Ethyl-1-(2-methylbenzimidazol-5-yl)-1H-pyrazole-4-carboxylic acid

72% yield.

APCIMS 269 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ0.97 (t, J=7.4, 3H), 2.49 (s, 3H), 2.81 (q,J=7.4, 2H), 7.38 (d, J=8.8, 1H), 7.50-7.55 (m, 2H), 7.88 (s, 1H), 12.36(s, 1H), 12.61 (bs, 1H).

EXAMPLE 28KK 5-Isopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carboxylic acid

90% yield

¹H NMR (400 MHz, DMSO-d₆) δ12.51 (s, 1H), 8.99 (t, J=1.6, 1H), 8.24 (d,J=8, 1H), 8.06 (s, 1H), 7.91 (t, J=8, 1H), 7.76 (d, J=7, 1H), 7.58 (dd,J=8, 4, 1H), 7.47 (d, J=8, 1H), 2.93 (quintet, J=7, 1H), 1.15 (m, 6H).

APCIMS 282 [M+1]⁺

EXAMPLE 28LL 1-(Quinolin-5-yl)-5-n-propyl-1H-pyrazole-4-carboxylic acid

91% yield

¹H NMR (400 MHz, CDCl₃) δ9.03 (d, J=4, 1H), 8.35 (d, J=8, 1H), 8.25 (s,1H), 7.86 (t, J=8, 1H), 7.66 (d, J=8, 1H), 7.61 (d, J=7, 1H), 7.47 (dd,J=8, 4, 1H), 2.81 (bs, 2H), 1.45 (sixtuplet, J=8, 2H), 0.75 (t, J=8,3H).

APCIMS 282 [M+1]⁻⁺

EXAMPLE 28MM5-Cyclopropyl-1-(2-dimethylaminosulfonylphenyl)-1H-pyrazole-4-carboxylicacid

88% yield

¹H NMR (300 MHz, DMSO-d₆) δ8.01 (m, 1H), 7.91 (s, 1H), 7.84 (m, 2H),7.60 (m, 1H), 2.64 (s, 6H), 1.81 (m, 1H), 0.59-0.77 (m, 4H).

APCIMS 336 [M+1]⁺

EXAMPLE 28NN5-Cyclopropyl-1-(2-methylsulfonylphenyl)-1H-pyrazole-4-carboxylic acid

79% yield

¹H NMR (300 MHz, DMSO-d₆) δ8.15 (m, 1H), 7.83-7.99 (m, 3H), 7.75 (m,1H), 3.34 (s, 3H), 1.86 (m, 1H), 0.5-0.9 (m, 4H).

APCIMS 307 [M+1]⁺

EXAMPLE 28OO5-Cyclopropyl-1-(2-methylaminosulfonylphenyl)-1H-pyrazole-4-carboxylicacid

70% yield

¹H NMR (300 MHz, DMSO-d₆) δ8.02 (m, 1H), 7.94 (s, 1H), 7.73-7.86 (m,2H), 7.69 (m, 1H), 6.88 (q, J=5, 1H), 2.50 (s, 3H), 1.89 (m, 1H),0.5-0.9 (m, 4H),

APCIMS 322 [M+1]⁺

EXAMPLE 28PP5-Cyclopropyl-1-(2,1,3-benzothiadiazol-4-yl)-1H-pyrazole-4-carboxylicacid

91% yield

¹H NMR (400 MHz, CDCl₃) δ8.21 (s, 1H), 8.14 (dd, J=7, 3, 1H), 7.73 (m,2H), 2.01 (m, 1H), 0.68 (m, 2H), 0.61 (m, 2H).

APCIMS 287 [M+1]⁺

EXAMPLE 28QQ 5-Methyl-1-(2,4-difluorophenyl)-1H-pyrazole-4-carboxylicacid

86% yield

¹H NMR (400 MHz, CDCl₃) δ8.10 (s, 1H), 7.43 (m, 1H), 7.03 (m, 2H), 2.45(s, 3H).

APCIMS 239 [M+1]⁺

EXAMPLE 28RR5-Cyclopropyl-1-(2-aminosulfonylphenyl)-1H-pyrazole-4-carboxylic acid

93% yield

¹H NMR (400 MHz, DMSO-d₆) δ12.34 (s, 1H), 8.03 (m, 1H), 7.93 (s, 1H),7.73 (m, 2H), 7.63 (m, 1H), 7.18 (s, 2H), 1.85 (m, 1H), 0.3-0.9 (m, 4H).

APCIMS 308 [M+1]⁺

EXAMPLE 28SS5-Cyclopropyl-1-(2-methylthiophenyl)-1H-pyrazole-4-carboxylic acid

97% yield

¹H NMR (400 MHz, DMSO-d₆) δ12.27 (s, 1H), 7.87 (s, 1H), 7.51 (t, J=8,1H), 7.41 .(d, J=8, 1H), 7.34 (d, J=8, 1H), 7.27 (t, J=7, 1H), 2.36 (s,3H), 1.83 (m, 1H), 0.65 (m, 4H).

APCIMS 275 [M+1]⁺

EXAMPLE 28TT 5-Methyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylic acid

84.4% yield.

¹H NMR (DMSO-d₆) d 2.62 (s, 3H); 7.66 (dd, 1H); 7.95 (dd, 1H); 8.06 (s,1H); 8.18-8.24 (m, 2H); 8.51 (d, 1H); 9.01 (t, 1H).

EXAMPLE 28UU 5-Cyclopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylicacid

75.5% yield.

¹H NMR (DMSO-d₆) d 0.49 (m, 2H); 0.86 (m, 2H); 2.2 (m, 1H); 7.64 (dd,1H); 8.01 (m, 1H); 8.03 (s, 1H); 8.16 (dd, 1H); 8.28 (d, 1H); 8.49 (d,1H); 9.0 (dd, 1H).

EXAMPLE 28VV 5-Cyclopropyl-1-(4-quinolinyl)-1H-pyrazole-4-carboxylicacid

78.2% yield.

¹H NMR (DMSO-d₆) d 0.56 (m, 2H); 0.64 (m, 2H); 1.91 (m, 1H); 7.49 (dd,1H); 7.68 (m, 1H); 7.8 (d, 1H); 7.88(m, 1H); 8.13 (s, 1H); 8.19 (d, 1H);9.11 (d, 1H).

EXAMPLE 28WW5-Methyl-1-(6-methoxy-5-quinolinyl)-1H-pyrazole-4-carboxylic acid

80.1% yield.

¹H NMR (DMSO-d₆) d 2.2 (s, 3H); 3.96 (s, 3H); 7.38 (dd,1H); 7.52 (m,1H); 7.92 (d, 1H); 8.08 (s, 1H); 8.3 (d, 1H); 8.86 (dd, 1H).

EXAMPLE 28XX5-Cyclopropyl-1-(6-methoxy-5-quinolinyl)-1H-pyrazole-4-carboxylic acid

41.6% yield.

¹H NMR (DMSO-d₆) d 0.45 (m, 2H); 0.65 (m, 2H); 1.72 (m, 1H); 3.91 (s,3H); 7.33 (d, 1H); 7.47 (m, 1H); 7.85 (d, 1H); 7.99 (s, 1H); 8.23 (d,1H); 8.8 (dd, 1H); 12.3 (s, 1H).

EXAMPLE 28YY5-Cyclopropyl-1-(6-methyl-5-quinolinyl)-1H-pyrazole-4-carboxylic acid

82.5% yield

¹H NMR (DMSO-d₆) d 0.52-0.77 (m, 4H); 1.7 (m, 1H); 2.19 (s, 3H); 7.4(dd, 1H); 7.57 (m, 1H); 7.85 (d, 1H); 8.15 (m,2H); 8.93 (t, 1H).

EXAMPLE 28ZZ 5-Ethyl-1-[2-methyl-6-quinolinyl)-1H-pyrazole-4-carboxylicacid

30% yield.

¹H NMR (DMSO-d₆) d 1.06 (t, 3H); 2.71 (s, 3H); 2.95 (q, 2H); 7.55 (d,1H); 7.82 (d, 1H); 8.02-8.13 (m, 3H); 8.38 (d, 1H).

EXAMPLE 28AAA 5-Ethyl-1-(6-methyl-5-quinolinyl)-1H-pyrazole-4-carboxylicacid

81.5% yield.

¹H NMR (DMSO-d₆) d 0.83 (t, 3H); 2.5-2.6 (2q, 2H): 2.15 (s, 3H); 7.33(q, 1H); 7.54 (q, 1H); 7.86 (dd, 1H); 8.14 (s, 1H); 8.19 (d, 1H); 8.94(d, 1H).

EXAMPLE 28BBB 5-Ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylic acid

71.9% yield.

¹H NMR (DMSO-d₆) d 1.04 (t, 3H); 2.96 (q, 2H); 7.63 (q, 1H); 7.85 (dd,1H); 8.01 (s, 1H); 8.17 (s+d, 2H); 8.49 (d, 1H); 8.99 (q, 1H).

EXAMPLE 28CCC 1-(2-Quinoxalinyl)-5-ethyl-1H-pyrazole-4-carboxylic acid

82% yield

¹H NMR (400 MHz, DMSO-d₆) δ9.42 (s, 1H), 8.14-8.11 (m, 2H), 8.00 (d, J=81 H), 7.91-7.83 (m, 2H), 3.44 (q, J=7, 2H), 1.29 (t, J=7, 3H).

APCIMS 267 [M−1]⁻

EXAMPLE 28DDD 1-(2-Benzimidazyl)-5ethyl-1H-pyrazole-4-carboxylic acid

66% yield

¹H NMR (400 MHz, DMSO-d₆) δ13.1 (s, 1H), 12.74 (bs, 1H), 8.12 (s, 1H),7.63 (d, J=6, 1H), 7.44 (d, J=6, 1H), 7.20(bs, 2H), 3.52 (q, J=7, 2H),1.21 (t, J=7, 3H).

APCIMS 257 [M+1]⁺

EXAMPLE 28EEE1-(2-Fluoromethyl-4-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylicacid

92% yield

¹H NMR (400 MHz, DMSO-d₆) δ12.43 (bs, 1H), 8.07 (s, 1H), 7.96-7.93 (m,2H), 7.76 (d, J=8, 1H), 1.76 (m, 1H), 0.68-0.74 (m, 4H).

APCIMS 331 [M+1]⁺

EXAMPLE 28FFF1-(2-Fluoro-6-trifluoromethylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylicacid

55% yield

¹H NMR (400 MHz, DMSO-d₆) δ12.50 (s, 1H), 7.98 (s, 1H), 7.92-7.82 (m,3H), 1.68 (m, 1H), 0.79-0.67 (m, 4H).

APCIMS 315 [M+1]⁺

EXAMPLE 28GGG1-(2-Trifluoromethyl-4-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxlicacid

86% yield

¹H NMR (300 MHz, DMSO-d₆) δ7.97-7.93 (m, 2H), 7.91-7.74 (m, 2H), 1.79(m, 1H), 0.75 (d, J=9, 4H).

APCIMS 315 [M+1]⁺

EXAMPLE 28HHH1-(1-Methylbenzimidaz-2-yl)-5-ethyl-1H-pyrazole-4-carboxylic acid

39% yield

¹H NMR (300 MHz, DMSO-d₆) δ8.17 (s, 1H), 7.77-7.70 (m, 2H), 7.47-7.32(m, 2H), 3.72 (s, 3H), 3.04 (q, J=7, 2H), 1.13 (t, J=7, 3H).

APCIMS 269 [M−1]⁻

EXAMPLE 28III 1-(2-Quinolinyl)-5-ethyl-1H-pyrazole-4-carboxylic acid

93% yield

¹H NMR (300 MHz, DMSO-d₆) δ12.62 (s, 1H), 8.57 (d, J=7, 1H), 8.05 (s,1H), 8.02-7.94 (m, 3H), 7.81 (t, J=5, 1H), 7.64 (t, J=5, 1H), 3.47 (q,J=5, 2H), 1.30-1.27 (m, 3H).

APCIMS 268 [M+1]⁺

EXAMPLE 28JJJ1-(2-Chloro-5-methylaminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylicacid

87% yield

¹H NMR (300 MHz, DMSO-d₆) δ8.67 (m, 1H), 8.06 (d, J=2, 1H), 8.04 (s,1H), 8.00 (s, 1H), 7.85 (d, J=9, 1 H), 2.79 (d, J=5, 3H), 1.88 (m, 1H),0.75-0.66 (m, 4H).

APCIMS 320 [M+1]⁺

EXAMPLE 28KKK1-(4-Benzimidazolyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid

83% yield

¹H NMR (400 MHz, DMSO-d₆) δ8.24-8.20 (m, 1H), 7.98-7.89 (m, 1H),7.77-7.64 (m, 1H), 7.33-7.21 (m, 2H), 1.96 (m, 1H), 0.64-0.47(m, 4H).

EXAMPLE 28LLL1-(2-chloro-5-iodophenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylic acid

86% yield

¹H NMR (300 MHz, DMSO-d₆) δ8.15 (s, 1H), 7.96-7.89 (m, 2H), 7.42 (dd,J=1.2, 8, 1H), 1.85 (m, 1H), 0.77-0.67 (m, 4H).

APCIMS 389 [M+1]⁺

EXAMPLE 28MMM1-(2-Chloro-5-aminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylicacid

31% yield

¹H NMR (300 MHz, DMSO-d₆) δ8.17 (s, 1H), 8.09-8.07 (m, 2H), 8.00 (s,1H), 7.84 (d, J=9, 1H), 7.66 (s, 1H), 1.85 (m, 1H), 0.76 (d, J=8, 2H),0.68 (d, J=5, 2H).

APCIMS 306 [M+1]⁺

EXAMPLE 28NNN1-(2-Chloro-5-dimethylaminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carboxylicacid

45% yield

¹H NMR (300 MHz, DMSO-d₆) δ7.98 (s, 1H), 7.79 (d, J=9, 1H), 7.72 (d,J=2, 1H), 7.63 (dd, J=2, 8, 1H), 2.99 (s, 3H), 2.93 (s, 3H), 1.89 (m,1H), 0.77-0.73 (m, 2H), 0;.67-0.65 (m, 2H).

APCIMS 334 [M+1]⁺

EXAMPLE 28OOO 1-Phenyl-4-cyclopropyl-1H-pyrazole-3-carboxylic acid

100% yield

APCIMS 229 [M+1]⁺

¹H NMR (300 MHz, DMSO-d₆) δ8.85 (s, 1H), 7.85-7.82 (m, 2H), 7.51-7.45(m, 2H), 7.32 (t, J=7, 1H), 2.57 (m, 1H), 0.99-0.90 (m, 4H).

EXAMPLE 28PPP 1-(1-Isoquinolyl-5-cyclopropyl-1H-pyrazole-4-carboxylicacid

75% yield

¹H NMR (400 MHz, DMSO-d₆) δ12.45 (s, 1H), 8.49 (d, J=6, 1H), 8.11 (d,J=8, 1H), 8.38 (d, J=6, 1H), 8.01 (s, 1H), 7.84 (t, J=8, 1H), 7.66 (t,J=8, 1H), 7.42 (d, J=9, 1H), 1.98 (m, 1H), 0.57 (d, J=6, 2H), 0.428 (d,J=3.6, 2H).

EXAMPLE 28QQQ 5-Isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylic acid

89.8% yield.

¹H NMR (DMSO-d₆) δ1.29 (d, 6H); 3.2 (m, 1H); 7.64 (q, 1H); 7.77 (dd,1H); 7.99 (s, 1H); 8.12 (s, 1H); 8.16 (dd, 1H); 8.5 (d, 1H); 8.99 (d,1H); 12.4 (bs, 1H).

EXAMPLE 28RRR 5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylic acid

86.4% yield.

¹H NMR (DMSO-d₆) δ0.68 (t, 3H); 1.42 (q, 2H); 2.97 (t, 2H); 7.62 (q,1H); 7.84 (t, 1H); 8.01 (s, 1H); 8.16 (d, 2H); 8.48 (d, 1H); 8.98 (d,1H); 12.45 (bs, 1H).

The title compounds of Examples 29A-29D were prepared using proceduresanalogous to that used for Example 8A.

EXAMPLE 29A[5-Cyclopropyl-1-(2,4-dichloro-6-[trifluoromethyl]phenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

14% yield.

APCIMS 406 [M+]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.83-0.86 (m, 4H); 1.79 (m, 1H); 8.21 (s,1H); 8.44 (bs, 3H); 8.71 (bs, 2H); 11.76 (s, 1H).

EXAMPLE 29B[5-Methoxymethyl-1-(5-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

13% yield

APCIMS 325 [M+1]⁺

¹H NMR (300 MHz, DMSO-d₆) δ9.12 (bs, 1H), 9.03 (m, 1H), 8.81 (bs, 2H),8.55 (bs, 2H), 8.36 (m, 1H), 7.06-8.06 (m, 4H), 4.61 (s, 2H), 3.01 (s,3H).

EXAMPLE 29C[1-(5-Methoxy-2-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

17% yield

APCIMS 334 [M+1]⁺

¹H NMR (300 MHz, DMSO-d₆) δ8.72 (bs, 2H), 8.67 (s, 1H), 8.43 (bs, 2H),7.63 (d, J=9, 1H), 7.29 (d, J=3, 1H), 7.21 (dd, J=3, 9, 1H), 3.82 (s,3H), 1.99 (m, 1H), 0.79 (d, J=9, 2H), 0.63 (d, J=4, 2H).

EXAMPLE 29D [1-(5-quinolinyl)-5-butyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

38% yield.

APCIMS 337 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.53 (ts, J=7.0, 3H), 1.01 (t, J=6.8, 2H),1.26 (s, 2H), 2.75 (s, 2H), 7.72-7.79(m, 2H), 7.92 (d, J=7.2, 1H), 8.03(t, J=7.8, 1H), 8.36 (d, J=8.4, 1H), 8.48 (bs, 2H), 8.81 (bs, 2H), 9.00(s, 1H), 9.12 (s, 1H), 12.169 (s, 1H).

EXAMPLE 30A[1-(Quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride monohydrate

A solution of guanidine hydrochloride (3.11 g, 32.6 mmol) in warmanhydrous ethanol (8 mL) under a nitrogen atmosphere was treated in oneportion with sodium methoxide (1.76 g, 32.6 mmol). The resulting slurrywas concentrated in vacuo. The residue was treated with anhydroustoluene (10 mL) and concentrated to dryness in vacuo (twice). Each timethe vacuum was released to a nitrogen atmosphere. The residue wastreated in one portion with ethyl1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carboxylate (1.00 g, 3.26mmol) in anhydrous ethanol (8 mL). The resulting mixture wasconcentrated in vacuo (rotatory evaporator, 80° C. water bath). Theresidue was treated with anhydrous toluene (10 mL) and the resultingmixture was concentrated in vacuo (three times). The resulting solid wastriturated with water (85 mL) and filtered. The solid was air-dried toprovide 0.880 g (

76% yield) of[1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinedihydrate.

APCIMS 321 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.51-0.53 (m, 4H), 1.88-1.95 (m, 1H),7.52-7.60 (m, 2H), 7.73 (d, J=8, 1H), 7.86 (t, J=9, 1H), 7.94 (s, 1H),8.16 (d, J=9, 1H), 8.95 (t, J=1.8, 1H).

A suspension of[1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinedihydrate (1.28 g, 3.59 mmol) in tetrahydrofuran (38.4 mL) with vigorousstirring was treated with concentrated hydrochloric acid (0.30 mL, 3.6mmol). The mixture became homogeneous within one minute and then a solidbegan to precipitate. The resulting mixture was stirred vigorously for 1h and filtered. The solid was air-dried to provide 1.11 g (82% yield) ofthe title compound.

APCIMS 321 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.42 (m, 2H), 0.59-0.61 (m, 2H), 1.88-1.95(m, 1H), 7.57 (dd, J=9, 4, 1H), 7.67 (d, J=4, 1H), 7.82 (d, J=7, 1H),7.90 (t, J=8, 1H), 8.22 (d, J=8, 1H), 8.38 (bs, 2H), 8.69 (bs, 2H), 8.72(s, 1H), 8.98 (dd, J=4, 1.4, 1H).

The title compounds of Examples 30B-30M were prepared using proceduresanalogous to that used for Example 30A.

EXAMPLE 30B[1-(Isoquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

14% yield

APCIMS 321 [M+1]⁺

¹H NMR (CDCl₃) δ1.9-2.0 (s, 1H), 8.80 (s, 1H)

EXAMPLE 30C[1-(Quinolin-5-yl)-5-benzyloxymethyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

41% yield

APCIMS 401 [M+1]⁺

¹H NMR (CDCl₃) δ4.16 (s, 2H), 8.87 (s, 1H)

EXAMPLE 30D[1-(Benzotriazole-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride monohydrate

49% yield

APCIMS 299 [M+1]⁺

¹H NMR (CDCl₃) δ0.99-1.03 (t, 3H), 8.61 (s, 1H)

EXAMPLE 30E [1-(Indazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride monohydrate

27% yield

APCIMS 298 [M+1]⁺

¹H NMR (CDCl₃) δ1.01-1.05 (t, 3H), 8.64 (s, 1H)

EXAMPLE 30F[1-(Quinolin-5-yl)-5-cyclobutyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

24% yield

APCIMS 335 [M+1]⁺

¹H NMR (CDCl₃ δ3.61-3.70 (m,1H), 8.75 (s, 1H)

EXAMPLE 30G[1-(6-Chloroquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

8% yield

APCIMS 354 [M+1]⁺

¹H NMR (CDCl₃) δ1.78-1.83 (m, 1H), 8.79 (s, 1H)

EXAMPLE 30H [1-(Indazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

39.3% yield

APCIMS 298 [M+1]⁺

¹H NMR (CDCl₃) δ0.99-10.5 (t, 3H), 8.70 (s, 1H)

EXAMPLE 30I[1-(1,4-Benzodioxan-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride monohydate

27% yield

APCIMS 316 [M+1]⁺

¹H NMR (CDCl₃) δ1.01-1.08 (t, 3H), 8.64 (s, 1H)

EXAMPLE 30J[1-(Quinolin-5-yl)-5-isobutyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

13.7%

APCIMS 337 [M+1]⁺

¹H NMR (CDCl₃) δ1.53-1.60 (m, 1H), 8.97 (s, 1H)

EXAMPLE 30K[1-(1,3-Benzodioxol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride monohydrate

9.4% yield

APCIMS 302 [M+1]⁺

¹H NMR (CDCl₃) δ0.99-1.02 (t, 3H), 8.63 (s, 1H)

EXAMPLE 30L[1-(8-Bromoquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride monohydrate

23% yield

APCIMS 401 [M+1]⁺

¹H NMR (CDCl₃) δ1.88-1.95 (m, 1H), 8.71 (s, 1H)

EXAMPLE 30M[1-(6-Trifluoromethylquinolin-8-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride monohydrate

18% yield

APCIMS 389 [M+1]⁺

¹H NMR (CDCl₃) δ1.80-1.87 (m, 1H), 8.80 (s, 1H)

The title compounds of Examples 31A-310 were prepared using proceduresanalogous to that used for Example 6A.

EXAMPLE31A [3-Methyl-1-(2-biphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

61% yield.

APCIMS 320 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ2.29 (s, 3H); 7.05 (m, 2H); 7.26 (m, 3H);7.54 (m, 4H); 7.64 (s, 1H); 8.35 (bs, 2H); 8.51 (bs, 2H), 8.85 (s, 1H),9.06 (s, 1H).

EXAMPLE 31B[5-Cyclopropyl-1-(2,1,3-benzothiadiazol-4-yl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

66% yield.

APCIMS 328 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.42 (m, 2H); 0.58 (m, 2H); 1.99 (m, 1H);7.81 (m, 2H); 8.30 (d, J=8.4, 1H); 8.40 (bs, 2H); 8.69 (s, 1H), 8.70(bs, 2H), 11.83 (s, 1H).

EXAMPLE 31C[5-Methyl-1-(2,4-difluorophenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

77% yield.

APCIMS 280 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ2.37 (s, 3H); 7.33 (m, 1H); 7.63-7.74 (m,2H); 8.48 (bs, 2H); 8.74 (bs, 2H); 8.83 (s, 1H); 12.09 (s, 1H).

EXAMPLE 31D[5-Cyclopropyl-1-(2-aminosulfonylphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

25% yield.

APCIMS 349 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.49-0.81 (m, 4H); 1.97.(m, 1H); 7.29 (bs,2H); 7.66 (d, J=7.2, 1H); 7.77 (m, 2H), 8.07 (d, J=8, 1H); 8.43 (bs,2H), 8.68 (s, 1H), 8.71 (bs, 2H), 11.81 (s, 1H).

EXAMPLE 31E[5-Cyclopropyl-1-(2-methylthiophenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

35% yield.

APCIMS 316 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.60 (m, 2H); 0.74 (m, 2H); 1.96 (m, 1H);7.31-7.98 (m, 4H); 8.40 (bs, 2H), 8.62 (s, 1H); 8.68 (bs, 2H).

EXAMPLE 31F1-(2-Pyrrol-1-ylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

12% yield.

APCIMS 335 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.32-0.53 (m, 4H), 1.04 (m, 1H), 6.09 (s,2H), 6.49 (s, 2H), 7.49-7.69 (m, 4H), 9.05 (bs, 5H), 10.80 (s, 1H).

EXAMPLE 31G [5-Methyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

92.4% yield.

¹H NMR (DMSO-d₆) δ2.64 (s, 3H); 7.86 (m, 1H); 8.11 (d, 1H); 8.33 (d,1H); 8.41 (bs+s, 3H); 8.74 (bs, 2H); 8.79 (d, 1H); 8.88 (s, 1H); 9.16(d, 1H).

EXAMPLE 31H[5-Cyclopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

98.8% yield.

hu 1H7NMR (DMSO-d₆) δ0.36 (m, 2H); 0.84 (m, 2H); 2.3 (m, 1H); 7.63 (s,1H); 7.95 (q,1H); 8.28 (dd, 1H); 8.43 (d, 1H); 8.56 (bs, 2H); 8.79 (bs,2H); 8.97 (d, 1H); 9.08 (s, 11H); 9.21 (d, 1H).

EXAMPLE 31I[5-Cyclopropyl-1-(4-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

72.4% yield.

¹H NMR (DMSO-d₆) d 0.41 (m, 2H); 0.65 (m, 2H); 1.99 (m, 1H); 7.52 (d,1H); 7.69 (m, 1H); 7.89 (m, 2H); 8.21 (d, 1H); 8.46 (bs, 2H); 8.76 (bs,2H); 8.85 (d, 1H); 9.13 (t, 1H); 12.1 (s, 1H).

EXAMPLE 31J[5-Methyl-1-(6-methoxy-5-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

55.9% yield.

¹H NMR (DMSO-d₆) d 2.24 (s, 3H); 3.96 (s, 3H); 7.57-7.67 (m, 2H); 8.0(dd, 1H); 8.37 (d, 1H); 8.43 (bs, 2H); 8.73 (bs, 2H); 8.88 (s, 1H); 8.94(d, 1H); 12.0 (s, 1H).

EXAMPLE 31K[5-Cyclopropyl-1-(6-methoxy-5-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

24.1% yield.

¹H NMR (DMSO-d₆) d 0.34 (m, 1H); 0.52 (m, 1H); 0.62 (m, 2H); 1.79 (m,1H); 3.94 (s, 3H); 7.51 (d, 1H); 7.6 (m, 1H); 7.95 (d, 1H); 8.32 (d,1H); 8.37 (bs, 2H); 8.68 (bs, 2H); 8.71 (s, 1H); 8.89 (d, 1H).

EXAMPLE 31L[5-Cyclopropyl-1-(6-methyl-5-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

70.7% yield.

¹H NMR (DMSO-d₆) d 0.49-0.72 (m, 4H); 1.81 (m, 1H); 2.51 (s, 3H); 7.75(m, 2H); 7.99 (dd, 1H); 8.33 (d, 1H); 8.51 (bs, 2H); 8.81 (bs, 2H); 8.92(s, 1H); 9.1 (t, 1H).

EXAMPLE 31M[5-Ethyl-1-(2-methyl-6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

47.6% yield.

¹H NMR (DMSO-d₆) δ1.11 (t, 3H); 2.89 (s, 3H); 3.0 (q, 2H); 7.86 (d, 1H);8.06 (d, 1H); 8.34-8.43 (m, 4H); 8.74-8.88 (m, 4H).

EXAMPLE 31N[5-Ethyl-1-(6-methyl-5-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

53.9% yield.

¹H NMR (DMSO-d₆) d 0.84 (t, 3H); 2.16 (s, 3H); 2.59 (2q, 2H); 7.61 (d,1H); 7.72 (q, 1H); 7.99 (d, 1H); 8.32 (d, 1H); 8.5 (bs, 2H); 8.81 (bs,2H); 9.07 (s+d, 2H).

EXAMPLE 31O [5-Ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride

63.7% yield.

¹H NMR (DMSO-d₆) d 1.11 (t, 3H); 3.04 (q, 2H); 7.91 (q, 1H); 8.08 (dd,1H); 8.38 (s, 1H); 8.42 (d, 1H); 8.5 (bs, 2H); 8.8 (bs, 2H); 8.86 (d,1H); 8.93 (s, 1H); 9.21 (d, 1H).

EXAMPLE 32A[5-Cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidinehydrochloride monohydrate

A mixture of5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carboxylic acid(1.00 g, 3.37 mmol) and thionyl chloride (0.739 mL, 10.1 mmol) washeated at reflux for 1 h under a nitrogen atmosphere, and concentratedin vacuo. The residue was treated with anhydrous toluene and the mixturewas concentrated in vacuo (twice). A solution of the resulting thick oilin anhydrous tetrahydrofuran (2.5 mL) was added dropwise to a vigorouslystirred mixture of guanidine hydrochloride (1.16 g, 12.0 mmol), sodiumhydroxide (2 N aqueous, 12 mL, 24 mmol) and tetrahydrofuran (6 mL) at23° C. The resulting mixture was heated at reflux for a 1 h, allowed tocool to room temperature and extracted twice with ethyl acetate. Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to afford 1.1 g of a pale pink solid.A suspension of the solid in water (3.2 mL) was treated withconcentrated hydrochloric acid (0.273 mL, 3.28 mmol) and stirred at roomtemperature for 1 h. The resulting suspension was filtered. The solidwas air-dried and recrystallized from water. The resulting crystallinesolid was air-dried to afford 0.98 g (74% yield) of the title compound.

APCIMS 338 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.57 (bs, 2H), 0.72-0.74 (m, 2H), 1.82-1.89(m, 1H), 7.71 (d, J=8, 1H), 7.80 (t, J=8, 1H), 7.86 (t, J=7, 1H), 7.97(d, J=7, 1H), 8.36 (bs, 2H), 8.60 (s, 1H), 8.62 (bs, 2H).

The title compounds of Examples 32B-32CCC were prepared using proceduresanalogous to that used for Example 16A and Example 32A.

EXAMPLE 32B[1-(2,3-Dimethoxyphenyl)-3-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

82% yield

APCIMS 304 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ2.43 (s, 3H), 3.73 (s, 3H), 3.85 (s, 3H),7.16 (m, 3H), 8.39 (bs, 2H), 8.64 (bs, 2H), 9.27 (s, 1H), 12.12 (s, 1H).

EXAMPLE 32C[1-(Naphthalen-1-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

84% yield

APCIMS 320 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.40-0.70 (m, 4H), 1.90 (m, 1H), 7.13 (d,J=8, 1H), 7.60 (m, 3H), 8.06 (d, J=8, 1H), 8.13 (d, J=8, 1H), 8.39 (bs,2H), 8.72 (m, 3H).

EXAMPLE 32D[1-(Naphthalen-2-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

83% yield

APCIMS 320 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.38 (d, J=4.8, 2H), 0.80 (d, J=8, 2H), 2.24(m, 1H), 7.57 (m, 2H), 7.72 (d, J=8.4, 1H), 8.03 (m, 3H), 8.18 (s, 1H),8.38 (bs, 2H), 8.64 (s, 1H), 8.70 (bs, 2H), 11.80. (s, 1H).

EXAMPLE 32E[1-(Naphthalen-2-yl)-3-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

83% yield

APCIMS 294 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ3.32 (s, 3H), 7.55 (m, 2H), 7.60-8.10 (m,4H), 8.30 (s, 1H), 8.40 (bs, 2H), 8.52 (bs, 2H), 9.80 (s, 1H), 12.12 (s,1H).

EXAMPLE 32F[1-(o-Biphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

72% yield.

APCIMS 346 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.25-0.70 (m, 4H), 1.12 (m, 1H), 7.00 (m,2H), 7.27 (m, 3H), 7.49-7.87 (m, 4H), 8.30 (bs, 2H), 8.56 (bs, 2H), 8.59(s, 1H), 11.58 (s, 1H).

EXAMPLE 32G[1-(5-Quinolinyl)-5-isopropyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

74% yield.

APCIMS 323 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ1.15 (d, J=6.8, 6H), 3.00 (m, 1H), 7.73 (s,2H), 7.91 (d, J=7.2, 1H), 8.04 (t, J=8, 1H), 8.38 (d, J=8.4, 1H), 8.51(bs, 2H), 8.84 (bs, 2H), 8.96 (s, 1H), 9.12 (m, 1H), 12.01 (s, 1H).

EXAMPLE 32H[1-(5-Quinolinyl)-5-n-propyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

78% yield.

APCIMS 323 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.61 (t, J=7.4, 6H), 1.33 (m, 2H), 2.73 (m,2H), 7.69-7.78 (m, 3H), 7.91 (d, J=7.6, 1H), 8.03 (t, J=7.2, 1H), 8.35(d, J=8, 1H), 8.47 (bs, 2.H), 8.81 (bs, 2H), 9.00 (s, 1H), 9.11 (m, 1H),12.15 (s, 1H).

EXAMPLE 32I [1-Phenyl-3-ethyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

63% yield.

APCIMS 258 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ1.22 (m, 3H), 2.88 (m, 2H), 7.38 (m, 1H),7.55 (m, 2H), 7.75 (m, 2H), 8.37 (bs, 2H), 8.52 (bs, 2H), 9.71 (s, 1H),12.10 (s, 1H).

EXAMPLE 32J[1-(2-Nitrophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

76% yield.

APCIMS 315 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.52 (bs, 2H), 0.80 (d, J=8.4, 2H), 2.04 (m,1H), 7.81 (d, J=7.6, 1H), 7.91 (bs, 2H), 8.16 (d, J=8, 1H), 8.47 (bs,2H), 8.67 (s, 1H), 8.72 (bs, 2H), 11.91 (s, 1H).

EXAMPLE 32K[1-(2-[Dimethylaminosulfonyl]phenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

72% yield.

APCIMS 377 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.49 (bs, 2H), 0.67 (d, J=6, 2H), 1.87 (m,1H), 2.62 (s, 6H), 7.61 (d, J=2, 1H), 7.83 (m, 2H), 7.98 (m, 1H), 8.40(bs, 2H), 8.64 (s, 1H), 8.68 (bs, 2H), 11.81 (bs, 1H).

EXAMPLE 32L[1-(2-[Methanesulfonyl]phenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

68% yield.

APCIMS 348 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.40-0.60 (m, 4H), 1.89 (m, 1H), 3.30 (s,3H), 7.73 (d, J=6.4, 1H), 7.88 (m, 2H), 8.11 (dd, J=8, 1.6, 1H), 8.36(bs, 2H), 8.64 (bs, 3H), 11.72 (s, 1H).

EXAMPLE 32M[1-(2-[Methylaminosulfonyl]phenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

44% yield.

APCIMS 363 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.48-0.76 (m, 4H), 1.93 (m, 1H), 2.4 (s, 3H),7.01 (s, 1H), 7.65 (m, 1H), 7.79 (m, 2H), 7.98 (m, 1H), 8.31 (bs, 2H),8.53 (s, 1H), 8.57 (bs, 2H), 11.58 (s, 1H).

EXAMPLE 32N[1-(2-Ethylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

48% yield.

APCIMS 298 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.61 (d, J=8.8, 2H), 0.71 (d, J=8.4, 2H),0.98 (t, J=7.4, 3H), 2.26 (d, J=7.2, 2H), 7.33 (m, 2H), 7.46 (m, 2H),8.35 (bs, 2H), 8.59 (s, 1H), 8.64 (bs, 2H), 11.70 (s, 1H).

EXAMPLE 32O[1-(2-Methylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

14% yield.

APCIMS 284 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.57 (bs, 2H), 0.70 (d, J=5.6, 2H), 1.96 (s,4H), 7.20-7.60 (m, 4H), 8.40 (bs, 2H), 8.65 (s, 1H), 8.71 (bs, 2H),11.81 (s, 1H).

EXAMPLE 32P[1-(2-Chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

74% yield.

APCIMS 304 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.55 (d, J=3.6, 2H), 0.72 (d, J=7.2, 2H),1.90 (m, 1H), 7.4-7.8 (m, 4H), 8.36 (bs, 2H), 8.61 (s, 1H), 8.63 (bs,2H), 11.74 (s, 1H).

EXAMPLE 32Q[1-(2-Trifluoromethoxyphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

87% yield.

APCIMS 354 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.48 (m, 2H), 0.74 (m, 2H), 1.89 (m, 1H),7.4-7.8 (m, 4H), 8.36 (bs, 2H), 8.62 (bs, 3H), 11.72 (s, 1H).

EXAMPLE 32R[1-(2-Fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

79% yield.

APCIMS 287 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.49 (d, J=4, 2H), 0.75 (d, J=6.8, 2H), 1.94(bs, 1H), 7.4-7.6 (m, 4H), 8.34 (bs, 2H), 8.58 (s, 1H), 8.61 (bs, 2H),11.71 (s, 1H),

EXAMPLE 32S[1-(2,1,3-Benzothiadiazol-4-yl)-3-methyl-1H-pyrazole-4-carbonyl]guanidine

73% yield.

APCIMS 302 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ2.49 (s, 3H), 7.7-7.81 (m, 1H), 7.98 (dd,J=8.4, 0.8, 1H), 8.13 (dd, J=7.6, 0.6, 1H), 9.36 (s, 1H).

EXAMPLE 32T[1-(Indazol-7-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

62% yield.

APCIMS 310 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.44 (dd, J=7.6, 5.2, 2H), 0.67-0.73 (m, 2H),2.11 (m, 1H), 7.26 (t, J=10, 1H), 7.53 (d, J=8.8, 1H), 7.94 (d, J=9.6,1H), 8.25 (s, 1H), 8.44 (bs, 2H), 8.79 (bs, 3H), 11.88 (s, 1H).

EXAMPLE 32U [1-(Indazol-7-yl)-3-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

63% yield.

APCIMS 284 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ2.53 (s, 3H), 7.23 (t, J=7.8, 1H), 7.57 (d,J=7.6, 1H), 7.78 (d, J=8.0, 1H), 8.23 (s, 1H), 8.40 (bs, 2H), 8.51 (bs,3H), 9.76 (s, 1H), 12.15 (bs, 1H).

EXAMPLE 32V[1-(Benzothiazol-2-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

85% yield.

APCIMS 315 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ1.29 (t, J=7.2, 3H), 3.61 (q, J=7.6, 2H),7.44-7.56 (m, 2H), 7.96 (d, J=8.4, 1H), 8.12 (d, J=8.0, 1H), 8.43 (bs,2H), 8.62 (bs, 2H), 8.84 (s, 1H), 12.01 (s, 1H).

EXAMPLE 32W[1-(2-Chloro-4-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

89% yield.

APCIMS 382 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.572 (dd, J=5.6, 2.0, 2H), 0.76 (dd, J=8.8,2.0, 2H), 1.91 (m, 1H), 3.36 (s, 3H), 7.94 (d, J=8.4, 1H), 8.05 (dd,J=8.4, 2.0 1H), 8.26 (s, 1H), 8.36 (bs, 2H), 8.63 (bs, 2H), 8.67 (s,1H), 11.80 (s, 1H).

EXAMPLE 32X[1-(2-Chloro-4-{methylsulfonylmethylenesulfonyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

72% yield.

APCIMS 460 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.53 (m, 2H), 0.77 (m, 2H), 1.94 (m, 1H),3.23 (s, 3H), 5.91 (s, 2H), 7.96-8.00 (m, 1H), 8.01-8.12 (m, 1H), 8.30(bs, 2H), 8.65 (bs, 2H), 8.66 (s, 1H), 11.11.73 (d, J=6.4, 1H).

EXAMPLE 32Y[1-(2-Chloro-5-{dimethylaminosulfonyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

85% yield.

APCIMS 411 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.52 (s, 2H), 0.74 (m, 2H), 1.93 (m, 1H),2.45 (s, 6H), 7.92-8.08 (m, 3H), 8.35 (bs, 2H), 8.64 (bs, 3H), 11.73 (s,1H).

EXAMPLE 32Z[1-(2-Chloro-5-{aminosulfonyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

9% yield.

APCIMS 383 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.57 (d, J=8.6, 2H), 0.78 (d, J=8.0, 2H),1.94 (m, 1H), 7.14 (t, J=51.0, 2H), 7.63 (s, 2H), 7.97 (m, 2H), 8.36(bs, 2H), 8.62 (bs, 3H), 8.64 (s, 1H), 11.73 (s, 1H).

EXAMPLE 32AA[1-(2-Chloro-5-{methylaminosulfonyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

61% yield.

APCIMS 397 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.53 (m, 2H), 0.72-0.76 (m, 2H), 1.92 (m,1H), 2.43 (d, J=5.2, 3H), 7.70 (d, J=5.2, 1H), 7.93-7.99 (m, 3H), 8.35(bs, 2H), 8.60 (bs, 2H), 8.61 (s, 1H), 11.70 (s, 1H).

EXAMPLE 32BB[1-(2,5-Dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

84% yield.

APCIMS 338 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.58 (s, 2H), 0.77 (d, J=7.2, 2H), 1.92 (m,1H), 7.70-7.77 (m, 2H), 7.90 (d, J=2.4, 1H), 8.37 (bs, 2H), 8.62 (bs,3H), 11.74 (s, 1H).

EXAMPLE 32CC[1-(2,4-Dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

62% yield.

APCIMS 338 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.54-0.56 (m, 2H), 0.73-0.78 (m, 2H), 1.90(m, 1H), 7.61-7.70 (m, 2H), 7.93 (s, 1H), 8.35 (bs, 2H), 8.60 (bs, 3H),11.72 (s, 1H).

EXAMPLE 32DD[1-(2,3-Dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

44% yield.

APCIMS 339 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.56-0.58 (m, 2H), 0.76 (s, 2H), 1.93 (m,1H), 7.57 (dt, J=7.6, 2.0, 1H), 7.67 (td, J=8.0, 1.6, 1H), 7.89 (td,J=8.0, 1.6, 1H), 8.42 (bs, 2H), 8.68 (bs, 3H), 11.86 (s, 1H).

EXAMPLE 32EE[1-(2-Chloro-5-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

86% yield.

APCIMS 382 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.57 (s, 2H), 0.77 (d, J=7.2, 2H), 1.94 (m,1H), 3.36 (s, 3H), 8.04 (d, J=8.4, 1H), 8.12 (d, J=8.4, 1H), 8.23 (s,1H)c 8.36 (bs, 2H), 8.61 (bs, 2H), 8.64 (s, 1H), 11.86 (s, 1H).

EXAMPLE 32FF[1-(Benzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

24% yield.

APCIMS 298 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ1.04 (t, J=7.2, 3H), 2.88 (q, J=7.2, 2H),7.63 (d, J=8.8, 1H), 8.01 (bs, 2H), 8.47 (bs, 2H), 8.78 (bs, 2H), 8.86(s, 1H), 9.55 (bs, 1H), 12.09 (s, 1H).

EXAMPLE 32GG[1-(2-Chloro-4-{dimethylaminosulfonyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

68% yield.

APCIMS 411 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.52 (d, J=4.4, 2H), 0.75 (d, J=8.4, 2H),1.93 (bs, 1H), 2.67 (s, 6H), 7.84-8.00 (m, 2H), 8.04 (s, 1H), 8.37 (bs,2H), 8.68 (bs, 3H), 11.82 (s, 1H).

EXAMPLE 32HH[1-(2-Chloro-4-{methylaminosulfonyl}phenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

26% yield.

APCIMS 397 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.55-0.58 (m, 2H), 0.75-0.80 (m, 2H), 1.93(m, 1H), 3.47 (s, 3H), 7.82 (t, J=4.8, 1H), 7.88-8.01 (m, 2H), 8.05 (s,1H), 8.34 (bs, 2H), 8.57 (bs, 2H), 8.06 (s, 1H), 11.66 (s, 1H).

EXAMPLE 32II[1-(Benzimidazol-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

16% yield.

APCIMS 310 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.37-0.41 (m, 2H), 0.75-0.82 (m, 2H), 2.19(m, 1H), 7.75 (d, J=8.8, 1H), 7.91-7.98 (m, 2H), 8.05 (s, 1H), 8.45 (bs,2H), 8.70 (s, 1H), 8.76 (bs, 2H), 9.51 (s, 1H), 11.95 (s, 1H).

EXAMPLE 32JJ [1-Benzyl-3-methyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

67% yield.

APCIMS 258 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ2.31 (s, 3H), 5.29 (s, 2H), 7.23-7.35 (m,5H), 8.47 (bs, 2H), 8.53 (bs, 2H), 8.55 (s, 1H), 11.73 (s, 1H.

EXAMPLE 32KK[1-(3-Chloroindazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

66% yield.

APCIMS 332 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ1.03 (d, J=10.4, 3H), 2.84 (d, J=7.6, 2H),7.49 (d, J=8.4, 1H), 7.72 (d. J=8.8, 1H), 7.79 (s, 1H), 8.41 (bs, 2H),8.73 (bs, 2H), 8.76 (s, 1H), 11.95 (s, 1H), 13.69 (s, 1H).

EXAMPLE 32LL[1-(1-Methylbenzimidazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

53% yield.

APCIMS 312 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ1.02 (m, 3H), 2.84 (d, J=7.6, 2H), 4.03 (s,3H), 7.64 (d, J=8.8, 1H), 8.00 (d, J=8.4, 1H), 8.20 (s, 1H), 8.47 (bs,2H), 8.78 (bs, 2H), 8.87 (s, 1H), 9.50 (bs, 1H), 12.12 (s, 1H).

EXAMPLE 32MM[1-(2-Methylbenzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

38% yield.

APCIMS 312 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ1.05 (bs, 3H), 2.79 (s, 3H), 2.88 (q, J=7.6,2H), 7.69 (dd, J=8.8, 1.6, 1H), 7.93 (m, 2H), 8.46 (bs, 2H), 8.77 (bs,2H), 8.85 (s, 1H), 12.09 (s, 1H).

EXAMPLE 32NN[1-(Benzothiazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride monohydrate

9.5% yield

APCIMS 315 [M+1]⁺

¹H NMR (CDCl₃) δ1.01-1.14 (t, 3H), 8.74 (s, 1H)

EXAMPLE 32OO[1-(2-Quinoxalinyl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

44% yield.

APCIMS 310 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ11.93 (s, 1H), 9.44 (s, 1H), 8.86 (s, 1H),8.64 (bs, 2H), 8.40 (bs, 2H), 8.16 (d, J=8, 1H), 8.043 (dd, J=2.4, 8,1H), 7.94-7.87 (m, 2H), 3.43 (q, J=6, 2H), 1.338 (t, J=7, 3H).

EXAMPLE 32PP[1-(2-Benzimidazyl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

44% yield.

APCIMS 298 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ12.15 (s, 1H), 8.97 (s, 1H), 8.73 (bs, 2H),8.47 (bs, 2H), 7.56 (dd, J=3, 6, 2H), 7.22 (dd, J=3.2, 6, 2H), 3.53 (q,J=7, 2H), 1.24 (t, J=7, 3H).

EXAMPLE 32QQ[1-(2-Trifluoromethyl-4-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

60% yield.

APCIMS 372 [M+1]⁺

¹H NMR (300 MHz, DMSO-d₆) δ8.68 (bs, 3H), 8.43 (bs, 2H), 8.14 (s, 1H),8.02 (d, J=8, 1H), 7.84 (d, J=9, 1H), 1.90 (m, 1H), 0.80 (d, J=8, 2H),0.693 (d, J=4, 2H).

EXAMPLE 32RR[1-(2-Fluoro-6-trifluoromethylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

71% yield

APCIMS 356 [M+1]⁺

¹H NMR (300 MHz, DMSO-d₆) δ8.71-8.44 (m, 5H), 8.00-7.90 (m, 3H), 1.82(m, 1H), 0.89-0.70 (m, 4H).

EXAMPLE 32SS[1-(2-Trifluoromethyl-4-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

58% yield

APCIMS 356 [M+1]⁺

¹H NMR (300 MHz, DMSO-d₆) δ8.67 (bs, 3H), 8.43 (bs, 2H), 7.99 (d, J=8,1H), 7.90-7.78 (m, 2H), 1.89 (m, 1H), 0.81-0.63 (m, 4H).

EXAMPLE 32TT[1-(1-Methylbenzimidaz-2-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

86% yield

APCIMS 312 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ12.10 (s, 1H), 8.96 (s, 1H), 8.71 (bs, 2H),8.44 (bs, 2H), 7.69 (dd, J=8,16, 2H) 7.40-7.29 (m, 2H), 3.68 (s, 3H),3.03 (q, J=7, 2H), 1.12 (t, J=7, 3H).

EXAMPLE 32UU [1-(2-Quinolinyl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

65% yield

APCIMS 309 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ11.86 (s, 1H), 8.79 (s, 1H), 8.65 (bs, 2H),8.61 (d, J=9, 1H), 8.38 (bs, 2H), 8.07 (d, J=8, 1 H), 8.01-7.96 (m, 2H),7.83 (m, 1H), 7.66 (t, J=7, 1H), 3.44 (q, J=7, 2H), 1.31 (t, J=7, 3H).

EXAMPLE 32VV[1-(2-Chloro-5-methylaminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

57% yield

APCIMS 359 [M−1]⁻

¹H NMR (400 MHz, DMSO-d₆) δ11.71 (s, 1H), 8.67 (m, 1H), 8.61 (bs, 3H),8.36 (bs, 2H), 8.04 (d, J=7, 1H) 8.03 (s, 1H), 7.84 (d, J=8, 1H), 2.60(d, J=4, 3H), 1.94 (m, 1H), 0.75 (d, J=7, 2H), 0.57 (m, 2H).

EXAMPLE 32WW[1-(4-Bezimidazolyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

22% yield

APCIMS 310 [M+1]⁺

¹H NMR (300 MHz, DMSO-d₆) δ9.19 (bs, 2H), 8.84 (d, J=2, 1H), 8.80 (s,1H), 8.45 (bs, 2H), 7.92 (m, 1H), 7.69-7.58 (m, 2H), 2.16 (m, 1H), 0.72(d, J=9, 2H), 0.44 (d, J=5, 2H).

EXAMPLE 32XX[1-(2-Chloro-5-iodophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

81% yield

APCIMS 430 [M+1]⁺

¹H NMR (300 MHz, DMSO-d₆) δ8.66 (bs, 2H), 8.64 (s, 1H), 8.40 (bs, 2H),8.18 (d, J=2, 1H), 7.94 (dd, J=2, 8, 1H), 7.45 (d, J=8, 1H), 1.94 (m,1H), 0.84-0.72 (m, 2H), 0.68-0.58 (m, 2H).

EXAMPLE 32YY[1-(2-Chloro-5-aminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

45% yield

APCIMS 347 [M+1]⁺

¹H NMR (300 MHz, DMSO-d₆) δ8.65 (bs, 2H), 8.62 (s, 1H), 8.37 (bs, 2H),8.20 (s, 1H), 8.10 (s, 1H), 8.02 (d, J=8, 1H), 7.87 (d, J=9, 1H), 7.68(s, 1H), 1.96 m, 1H), 0.80 (d, J=8, 2H), 0.61 (d, J=3, 2H).

EXAMPLE 32ZZ[1-(2-Chloro-5-dimethylaminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

49% yield

APCIMS 375 [M+1]⁺

¹H NMR (300 MHz, DMSO-d₆) δ8.60 (bs, 3H), 8.38 (bs, 2H), 7.82 (d, J=8,1H), 7.76 (d, J=2, 1H), 7.66 (m, 1H), 2.99 (s, 3H), 2.93 (s, 3H), 1.96(m, 1H), 0.79 (d, J=9, 2H), 0.60 (d, J=4, 2H).

EXAMPLE 32AAA [1-Phenyl-4-cyclopropyl-1H-pyrazole-3-carbonyl]guanidinehydrochloride

22% yield

APCIMS 270 [M+1]⁺

¹H NMR (300 MHz, DMSO-d6) δ9.56 (bs, 1H), 8.45 (bs, 4H), 7.74 (d, J=8,2H), 7.56 (t, J=8, 2H), 7.40 (t, J=7, 1H), 2.62 (m, 1H), 0.99-0.94 (m,4H).

EXAMPLE 32BBB[1-(1-Isoquinolyl-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinedihydrochloride

69% yield

APCIMS 321 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ11.99 (s, 1H), 8.79 (s, 1H), 8.77 (bs, 2H),8.51 (d, J=6, 1H), 8.49 (bs, 2H), 8.13 (d, J=8, 1H), 8.10 (d, J=6, 1H),7.85 (dd, J=7, 8, 1H), 7.9-7.6 (bs, 1H), 7.69 (dd, J=7, 8, 1H), 7.46 (d,J=8, 1H), 2.05 (m, 1H), 0.61-0.57 (m, 2H), 0.37-0.33 (m, 2H).

EXAMPLE 32CCC[1-(2,3-Dimethoxyphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidinehydrochloride

38% yield.

APCIMS 330 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ0.57 (d, J=4.8, 2H), 0.72 (d, J=8.4, 2H),1.91 (m, 1H), 3.57 (s, 3H), 3.86 (s, 3H), 6.97 (d, J=8, 1H), 7.22 (m,2H), 8.34 (bs, 2H), 8.56 (s, 1H), 8.65 (bs, 2H), 11.67 (s, 1H).

EXAMPLE 33AN-tert-Butoxycarbonyl-N′-[5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine

To a solution of 5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carboxylicacid (336.7 mg, 1.2 mmol) in 5 ml dimethylformamide was addedN,N-diisopropylethylamine (0.42 ml, 2.39 mmol),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent) (582 mg, 1.32 mmol) and tert-butoxycarbonylguanidine (210mg, 1.32 mmol). The resulting solution was stirred at room temperaturefor 2 h, then heated to 60° C. for 2 h. The reaction mixture was thencooled to room temperature and concentrated to dryness in vacuo. Thesolid residue was partitioned between ethyl acetate and water. The ethylacetate layer was washed with brine, dried (sodium sulfate) andconcentrated to dryness in vacuo. The solid residue was triturated withmethanol (1.5 ml), filtered, washed with diethyl ether and dried toyield the title compound as a white solid (114.3 mg, 22.5% yield).

¹H NMR (DMSO-d₆) δ1.27 (d, 6H); 1.42 (s, 9H); 3.28 (m, 1H); 7.62 (q,1H); 7.74 (q, 1H); 8.08-8.15 (m, 4H); 8.47 (d, 1H); 8.98 (d, 1H); 9.21(bs, 1H); 10.9 (bs, 1H).

The title compound of Example 33B was obtained using a procedureanalogous to that used for Example 33A.

EXAMPLE 33BN-tert-butoxycarbonyl-N′[5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine

58.9% yield.

¹H NMR (DMSO-d₆) δ0.73 (t, 3H); 1.24 (d, 2H); 1.47 (s, 9H); 3.08 (t,2H); 7.66 (q, 1H); 7.86 (q, 1H); 8.18 (m, 3H); 8.51 (s+d, 2H); 9.01 (t,1H); 9.39 (bs, 1H); 11.0 (bs, 1H).

EXAMPLE 34A[5-Isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinetrifluoroacetate

A solution ofN-tert-butoxycarbonyl-N′-[5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine(114.3 mg, 0.27 mmol) in 2 ml of dichloromethane containing 20%trifluoroacetic acid was stirred at room temperature overnight andtreated with ether. The resulting precipitate was filtered, yielding thetitle compound as a white solid (104.3 mg,

70% yield).

¹H: NMR (DMSO-d₆) δ1.29 (d, 6H); 3.23 (m, 1H); 7.68 (q, 1H); 7.8 (dd,1H); 8.18-8.55 (m, 7H); 9.04 (t, 1H); 11.1 (s, 1H).

The title compound of Example 34B was obtained using a procedureanalogous to that used for Example 34A.

EXAMPLE 34B [5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidinetrifluoroacetate

81.2% yield.

¹H NMR (DMSO-d₆) δ0.72 (t, 3H); 1.47 (d, 2H); 2.97 (t, 2H); 7.67 (t,1H); 7.87 (d, 1H), 8.19-8.37 (m, 7H); 8.53 (d, 1H); 9.03 (s, 1H); 11.1(s, 1H).

What is claimed is:
 1. A compound having the Formula I

a prodrug thereof or a pharmaceutically acceptable salt of said compoundor of said prodrug, wherein either (i) Z is

wherein R¹ is (C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl, said(C₃-C₇)cycloalkyl optionally substituted with from one to threefluorines, said R¹ substituent optionally mono- or di-substitutedindependently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinylor (C₁-C₄)alkylsulfonyl; and R² is (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, M orM(C₁-C₄)alkyl, any of said previous (C₁-C₄)alkyl moieties optionallyhaving from one to nine fluorines; said (C₁-C₄)alkyl or(C₃-C₄)cycloalkyl optionally mono-or di-substituted independently withhydroxy, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl, (C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl; and said (C₃-C₄)cycloalkyl optionallyhaving from one to seven fluorines; wherein M is a partially saturated,fully saturated or fully unsaturated five to eight membered ringoptionally having one to three heteroatoms selected independently fromoxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated three to sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen,with the proviso that M is not phenyl; said M is optionally substituted,on one ring if the moiety is monocyclic, or one or both rings if themoiety is bicyclic, on carbon or nitrogen with up to three substituentsindependently selected from R⁶, R⁷ and R⁸, wherein one of R⁶, R⁷ and R⁸is optionally a partially saturated, fully saturated, or fullyunsaturated three to seven membered ring optionally having one to threeheteroatoms selected independently from oxygen, sulfur and nitrogenoptionally substituted with (C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸are optionally hydroxy, nitro, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl, wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl,(C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylaminoor (C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines; or (ii) Z is

wherein R¹ is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl orphenyl(C₁-C₄)alkyl, said (C₁-C₄)alkyl optionally substituted with fromone to nine fluorines, said R¹ substituent optionally mono- ordi-substituted independently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl or (C₁-C₄)alkylsulfonyl; and R² is a five to sixmembered nonaromatic heterocyclic ring having one to two heteroatomsselected independently from nitrogen, sulfur and oxygen or R² isunsubstituted (C₁-C₄)alkyl or unsubstituted (C₃-C₇)cycloalkyl; or R² isphenyl(C₁-C₄)alkyl, or a bicyclic ring consisting of two fused fiveand/or six membered partially saturated, fully saturated or fullyunsaturated rings taken independently having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen, said R²substituents optionally substituted on carbon or nitrogen with up tothree substituents independently selected from R⁶, R⁷ and R⁸, whereinone of R⁶, R⁷ and R⁸ is optionally a partially saturated, fullysaturated, or fully unsaturated three to seven membered ring optionallyhaving one to three heteroatoms selected independently from oxygen,sulfur and nitrogen optionally substituted with (C₁-C₄)alkyl andadditionally R⁶, R⁷ and R⁸ are optionally hydroxy, nitro, halo,(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl, wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl,(C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylaminoor (C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines, or (iii) Z is

wherein R⁴ is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl orphenyl(C₁-C₄)alkyl, said (C₁-C₄)alkyl optionally substituted with fromone to nine fluorines, said R⁴ substituent optionally mono- ordi-substituted independently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl or (C₁-C₄)alkylsulfonyl; and R⁵ is a five to sixmembered nonaromatic heterocyclic ring having one to two heteroatomsselected independently from nitrogen, sulfur and oxygen or R⁵ isunsubstituted (C₁-C₄)alkyl or unsubstituted (C₃-C₇)cycloalkyl; or R⁵ isphenyl(C₁-C₄)alkyl, or a bicyclic ring consisting of two fused fiveand/or six membered partially saturated, fully saturated or fullyunsaturated rings taken independently having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen, said R⁵substituents optionally substituted on carbon or nitrogen with up tothree substituents independently selected from R⁶, R⁷ and R⁸, whereinone of R⁶, R⁷ and R⁸ is optionally a partially saturated, fullysaturated, or fully unsaturated three to seven membered ring optionallyhaving one to three heteroatoms selected independently from oxygen,sulfur and nitrogen optionally substituted with (C₁-C₄)alkyl andadditionally R⁶, R⁷ and R⁸ are optionally hydroxy, nitro, halo,(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl, wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl,(C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylaminoor (C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines; or (iv) Z is

wherein R² is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, M or M(C₁-C₄)alkyl, anyof said previous (C₁-C₄)alkyl moieties optionally having from one tonine fluorines; said (C₁-C₄)alkyl or (C₃-C₄)cycloalkyl optionallymono-or di-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,(C₁-C₄)alkyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl; and said (C₃-C₄)cycloalkyl optionallyhaving from one to seven fluorines; wherein M is a partially saturated,fully saturated or fully unsaturated five to eight membered ringoptionally having one to three heteroatoms selected independently fromoxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated three to sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen;said M is optionally substituted, on one ring if the moiety ismonocyclic, or one or both rings if the moiety is bicyclic, on carbon ornitrogen with up to three substituents independently selected from R⁶,R⁷ and R⁸, wherein one of R⁶, R⁷ and R⁸ is optionally a partiallysaturated, fully saturated, or fully unsaturated three to seven memberedring optionally having one to three heteroatoms selected independentlyfrom oxygen, sulfur and nitrogen optionally substituted with(C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸ are optionally hydroxy,nitro, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl, wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl,(C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylaminoor (C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines; and R³ is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl orphenyl(C₁-C₄)alkyl, said (C₁-C₄)alkyl optionally substituted with fromone to nine fluorines, said R³ substituent optionally mono- ordi-substituted independently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or (C₁-C₄)alkyl with theproviso that no single ring within a bicyclic ring can have more thanthree heteroatoms within the single ring.
 2. A compound as recited inclaim 1 wherein Z is

wherein R¹ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl; and R² is quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, quinazolinyl,benzopyranyl, benzothiophenyl, benzodioxanyl or benzodioxolyl, said R²substituent optionally mono-substituted or the pharmaceuticallyacceptable salts thereof.
 3. A compound as recited in claim 2 wherein R²is 5-quinolinyl; and R¹ is cyclopropyl or the pharmaceuticallyacceptable salts thereof.
 4. A compound as recited in claim 2 wherein R²is 8-quinolinyl; and R¹ is cyclopropyl or the pharmaceuticallyacceptable salts thereof.
 5. A compound as recited in claim 2 wherein R²is 6-quinolinyl; and R¹ is methyl or the pharmaceutically acceptablesalts thereof.
 6. A compound as recited in claim 1 wherein Z is

wherein R² is quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl, benzodioxanylor benzodioxolyl, said R² substituent optionally mono-substituted; andR¹ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl or the pharmaceuticallyacceptable salts thereof.
 7. A compound as recited in claim 6 wherein R²is 5-isoquinolyl; and R¹ is methyl or the pharmaceutically acceptablesalts thereof.
 8. A compound as recited in claim 1 wherein Z is

wherein R² is phenyl, optionally mono- or di-substituted; and R³ is(C₁-C₄)alkyl or (C₃-C₇)cycloalkyl or the pharmaceutically acceptablesalts thereof.
 9. A compound as recited in claim 1 wherein the compoundis [2-methyl-5-phenyl-2H-pyrazole-3-carbonyl]guanidine; or[2-methyl-5-(naphthalen-1-yl)-2H-pyrazole-3-carbonyl]guanidine or thepharmaceutically acceptable salts thereof.
 10. A compound as recited inclaim 8 wherein R² is phenyl; and R³ is methyl or the pharmaceuticallyacceptable salts thereof.
 11. A compound as recited in claim 1 wherein Zis

wherein R² is naphthalenyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinoxalinyl, quinazolinyl, benzopyranyl, benzothiophenyl,benzodioxanyl or benzodioxolyl, said R² substituent optionallymono-substituted; and R³ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl or thepharmaceutically acceptable salts thereof.
 12. A compound as recited inclaim 11 wherein R² is 1-naphthalenyl; and R³ is methyl or thepharmaceutically acceptable salts thereof.
 13. A compound as recited inclaim 1 wherein Z is

wherein R⁴ is (C₁-C₄)alkyl or (C₃-C₇)cycloalkyl; and R⁵ is quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, quinazolinyl,benzopyranyl, benzothiophenyl, benzodioxanyl or benzodioxolyl, said R⁵substituents optionally mono-substituted or the pharmaceuticallyacceptable salts thereof.
 14. A compound as recited in claim 13 whereinR⁵ is 5-isoquinolinyl; and R⁴ is methyl or the pharmaceuticallyacceptable salts thereof.
 15. A compound as recited in claim 13 whereinR⁵ is 5-quinolinyl; and R⁴ is methyl or the pharmaceutically acceptablesalts thereof.
 16. A method of reducing tissue damage resulting fromischemia comprising administering to a mammal in need of such treatmenta therapeutically effective amount of a compound of claim 1 or a prodrugthereof or a pharmaceutically acceptable salt of said compound or ofsaid prodrug.
 17. A method as recited in claim 16 wherein the tissue iscardiac, brain, liver, kidney, lung, gut, skeletal muscle, spleen,pancreas, nerve, spinal cord, retina tissue, the vasculature, orintestinal tissue.
 18. A method as recited in claim 17 wherein theamount of the Formula I compound is about 0.01 mg/kg/day to about 50mg/kg/day.
 19. A method as recited in claim 18 wherein the mammal is afemale or male human.
 20. A method as recited in claim 19 wherein saidtissue is heart tissue.
 21. A method as recited in claim 19 wherein saidtissue is brain tissue.
 22. A method as recited in claim 19 wherein saidtissue is liver tissue.
 23. A method as recited in claim 19 wherein saidtissue is kidney tissue.
 24. A method as recited in claim 19 whereinsaid tissue is lung tissue.
 25. A method as recited in claim 19 whereinsaid tissue is gut tissue.
 26. A method as recited in claim 19 whereinsaid tissue is skeletal muscle tissue.
 27. A method as recited in claim19 wherein said tissue is spleen tissue.
 28. A method as recited inclaim 19 wherein said tissue is pancreas tissue.
 29. A method as recitedin claim 19 wherein said tissue is retina tissue.
 30. A method asrecited in claim 19 wherein the compound is administeredprophylactically.
 31. A method as recited in claim 19 wherein thecompound is administered prior to surgery.
 32. A method as recited inclaim 19 wherein the compound is administered prior to cardiac surgery.33. A method as recited in claim 19 wherein the compound is administeredduring surgery.
 34. A method as recited in claim 19 wherein the compoundis administered during cardiac surgery.
 35. A method as recited in claim19 wherein the compound is administered within twenty-four hours aftersurgery.
 36. A method as recited in claim 19 wherein the compound isadministered within twenty four hours after cardiac surgery.
 37. Amethod as recited in claim 19 wherein the tissue damage resulting fromischemia is ischemic damage and is incurred during organtransplantation.
 38. A method as recited in claim 19 wherein thecompound is administered to prevent perioperative myocardial ischemicinjury.
 39. A pharmaceutical composition which comprises atherapeutically effective amount of a compound of claim 1 or a prodrugthereof or a pharmaceutically acceptable salt of said compound or ofsaid prodrug and a pharmaceutically acceptable carrier.
 40. Apharmaceutical composition for the reduction of tissue damage resultingfrom ischemia which comprises a therapeutically effective amount of acompound of claim 1 or a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or of said prodrug and apharmaceutically acceptable carrier.
 41. A method as recited in claim 19wherein the compound is administered prior to, during and after surgery.42. A method as recited in claim 19 wherein the compound is administeredprior to, during and after cardiac surgery.
 43. A compound as recited inclaim 1 wherein Z is

R¹ is (C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl, said(C₃-C₇)cycloalkyl optionally substituted with from one to threefluorines, said R¹ substituent optionally mono- or di-substitutedindependently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinylor (C₁-C₄)alkylsulfonyl; and R² is (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, M orM(C₁-C₄)alkyl, any of said previous (C₁-C₄)alkyl moieties optionallyhaving from one to nine fluorines; said (C₁-C₄)alkyl or(C₃-C₄)cycloalkyl optionally mono-or di-substituted independently withhydroxy, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,(C₁-C₄)alkylsulfonyl, (C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl; and said (C₃-C₄)cycloalkyl optionallyhaving from one to seven fluorines; wherein M is a partially saturated,fully saturated or fully unsaturated five to eight membered ringoptionally having one to three heteroatoms selected independently fromoxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated three to sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen withthe proviso that M is not phenyl; said M is optionally substituted, onone ring if the moiety is monocyclic, or one or both rings if the moietyis bicyclic, on carbon or nitrogen with up to three substituentsindependently selected from R⁶, R⁷ and R⁸, wherein one of R⁶, R⁷ and R⁸is optionally a partially saturated, fully saturated, or fullyunsaturated three to seven membered ring optionally having one to threeheteroatoms selected independently from oxygen, sulfur and nitrogenoptionally substituted with (C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸are optionally hydroxy, nitro, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl, wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl,(C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylaminoor (C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines or the pharmaceutically acceptable salts thereof. 44.A compound as recited in claim 1 wherein the compound is[1-(Naphthalen-1-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine or apharmaceutically acceptable salt thereof.
 45. A compound as recited inclaim 43 wherein R¹ is cyclopropyl; and R² is 1-naphthalenyl or apharmaceutically acceptable salt thereof.
 46. A compound as recited inclaim 43 wherein R¹ is (C₃-C₇)cycloalkyl; and R² is a five to sixmembered monocyclic aromatic ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen withthe proviso that R² is not phenyl; said R² ring is optionallymono-substituted on carbon or nitrogen with a fully saturated or fullyunsaturated five to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,said ring optionally mono-substituted with (C₁-C₄)alkyl said R² ring isalso optionally mono- or di-substituted independently on carbon ornitrogen with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, (C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— ordi-N,N—(C₁-C₄)alkylamino are optionally mono-substituted with hydroxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tonine fluorines or the pharmaceutically acceptable salts thereof.
 47. Acompound as recited in claim 43 wherein R² is a five to six memberednonaromatic heterocyclic ring having one to two heteroatoms selectedindependently from nitrogen, sulfur and oxygen or R² is unsubstituted(C₁-C₄)alkyl, unsubstituted (C₃-C₇)cycloalkyl or phenyl(C₁-C₄)alkyl,wherein said phenyl(C₁-C₄)alkyl is optionally mono-or di-substitutedindependently with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, mono-N— or di-N,N—(C₁¹-C₄)alkylamino, carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl,(C₁-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkylaminosulfonyl,wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino substituents are optionally mono-substitutedwith hydroxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tofive fluorines; or pharmaceutically acceptable salt thereof.
 48. Acompound as recited in claim 46 wherein R² is a bicyclic ring consistingof two fused five and/or six membered partially saturated, fullysaturated or fully unsaturated rings taken independently having one tofour heteroatoms selected independently from nitrogen, sulfur andoxygen, said R² substituent optionally substituted on carbon or nitrogenwith up to three substituents independently selected from R⁶, R⁷ and R⁸,wherein one of R⁶, R⁷ and R⁸ is optionally a partially saturated, fullysaturated, or fully unsaturated three to seven membered ring optionallyhaving one to three heteroatoms selected independently from oxygen,sulfur and nitrogen optionally substituted with (C₁-C₄)alkyl andadditionally R⁶, R⁷ and R⁸ are optionally hydroxy, nitro, halo,(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl, wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl,(C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylaminoor (C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines, or a pharmaceutically acceptable salt thereof.
 49. Acompound as recited in claim 48 wherein R¹ is (C₃-C₇)cycloalkyl; and R²is a bicyclic ring consisting of two fused five and/or six memberedpartially saturated, fully saturated or fully unsaturated rings takenindependently having one to three heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen, said R² bicyclic ring is optionallymono-substituted on carbon or nitrogen with a fully saturated or fullyunsaturated five to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,said ring optionally mono-substituted with (C₁-C₄)alkyl said R² bicyclicring is also optionally mono- or di-substituted independently on carbonor nitrogen with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, (C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— ordi-N,N—(C₁-C₄)alkylamino are optionally mono-substituted with hydroxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tonine fluorines or a pharmaceutically acceptable salt thereof.
 50. Acompound as recited in claim 49 wherein R¹ is cyclopropyl; and R² is aquinazolinyl, phthalazinyl, quinolinyl, isoquinolinyl, cinnolinyl,benzodioxanyl, quinoxalinyl, benzopyranyl, benzothiophenyl,benzodioxolyl, benzimidazolyl, indazolyl, indolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,benzoxadiazolyl or benzothiadiazolyl ring, wherein said R² bicyclic ringis optionally mono- or di-substituted independently on carbon ornitrogen with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, mono-N— or di-N,N—(C₁-C₄)alkylamino substituents areoptionally mono-substituted with hydroxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto five fluorines; or a pharmaceutically acceptable salt thereof.
 51. Acompound as recited in claim 50 wherein R² is a quinolinyl;isoquinolinyl, indazolyl or benzimidazolyl ring, wherein said R²bicyclic ring is optionally mono- or di-substituted independently withhydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl,(C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl,mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl, wherein said (C₁-C₄)alkoxy or(C₁-C₄)alkyl substituents are optionally mono-substituted with hydroxy,(C₁-C₄)alkanoylamino, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl,(C₁-C₄)alkylsulfonyl or mono-N— or di-N,N—(C₁-C₄)alkylaminosulfonyl oroptionally substituted with one to five fluorines; or a pharmaceuticallyacceptable salt thereof.
 52. A compound as recited in claim 1 whereinthe compound is[5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine;[5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidine; orpharmaceutically acceptable salt thereof.
 53. A compound as recited inclaim 1 wherein the compound is[1-(8-bromoquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(6-chloroquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(indazol-7-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(benzimidazol-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[1-(1-isoquinolyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;[5-cyclopropyl-1-(4-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine; or apharmaceutically acceptable salt thereof.
 54. A compound as recited inclaim 51 wherein R² is 8-bromoquinolin-5-yl or a pharmaceuticallyacceptable salt thereof.
 55. A compound as recited in claim 51 whereinR² is 6-chloroquinolin-5-yl or the pharmaceutically acceptable saltsthereof.
 56. A compound as recited in claim 51 wherein R² isindazol-7-yl or the pharmaceutically acceptable salts thereof.
 57. Acompound as recited in claim 51 wherein R² is benzimidazol-5-yl or thepharmaceutically acceptable salts thereof.
 58. A compound as recited inclaim 51 wherein R² is 1isoquinolyl or the pharmaceutically acceptablesalts thereof.
 59. A compound as recited in claim 51 wherein R² is4-quinolinyl or the pharmaceutically acceptable salts thereof.
 60. Acompound as recited in claim 1 wherein Z is

R¹ is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl,said (C₁-C₄)alkyl optionally substituted with from one to ninefluorines, said R¹ substituent optionally mono- or di-substitutedindependently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinylor (C₁-C₄)alkylsulfonyl; and R² is a five to six membered nonaromaticheterocyclic ring having one to two heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen or R² is unsubstituted (C₁-C₄)alkyl orunsubstituted (C₃-C₇)cycloalkyl; or R² is phenyl(C₁-C₄)alkyl, or abicyclic ring consisting of two fused five and/or six membered partiallysaturated, fully saturated or fully unsaturated rings takenindependently having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen, said R² substituents optionally substitutedon carbon or nitrogen with up to three substituents independentlyselected from R⁶, R⁷ and R⁸, wherein one of R⁶, R⁷ and R⁸ is optionallya partially saturated, fully saturated, or fully unsaturated three toseven membered ring optionally having one to three heteroatoms selectedindependently from oxygen, sulfur and nitrogen optionally substitutedwith (C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸ are optionally hydroxy,nitro, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl, wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl,(C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylaminoor (C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines, or a pharmaceutically acceptable salt thereof.
 61. Acompound as recited in claim 60 wherein R¹ is (C₁-C₄)alkyl; and R² is abicyclic ring consisting of two fused five and/or six membered partiallysaturated, fully saturated or fully unsaturated rings takenindependently having one to three heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen, said R² bicyclic ring is optionallymono-substituted on carbon or nitrogen with a fully saturated or fullyunsaturated five to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,said ring optionally mono-substituted with (C₁-C₄)alkyl, said R²bicyclic ring is also optionally mono- or di-substituted independentlyon carbon or nitrogen with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, (C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— ordi-N,N—(C₁-C₄)alkylamino are optionally mono-substituted with hydroxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tonine fluorines or a pharmaceutically acceptable salt thereof.
 62. Acompound as recited in claim 61 wherein R² is a quinazolinyl,phthalazinyl, quinolinyl, isoquinolinyl, cinnolinyl, benzodioxanyl,quinoxalinyl, benzopyranyl, benzothiophenyl, benzodioxolyl,benzimidazolyl, indazolyl, indolyl, benzotriazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl orbenzothiadiazolyl ring, wherein said R² bicyclic ring is optionallymono- or di-substituted independently with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, mono-N— or di-N,N—(C₁-C₄)alkylamino substituents areoptionally mono-substituted with hydroxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto five fluorines; or a pharmaceutically acceptable salt thereof.
 63. Acompound as recited in claim 1 wherein the compound is[1(indazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(indazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(benzimidazol-5yl)-5ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(1-methylbenzimidazol-6-yl)-5ethyl-1H-pyrazole-4-carbonyl]guanidine[1-(5-quinolinyl)-5-n-propyl-1H-pyrazole-4-carbonyl]guanidine;[1-(5-quinolinyl)-5-isopropyl-1H-pyrazole-4-carbonyl]guanidine;[5-ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;[1-(2-methylbenzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(1,4-benzodioxan-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(benzotriazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(3-chloroindazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;[1-(5-quinolinyl-5-butyl-1H-pyrazole-4-carbonyl]guanidine;[5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;[5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine; or apharmaceutically acceptable salt thereof.
 64. A compound as recited inclaim 62 wherein R¹ is ethyl; and R² is indazol-6-yl or thepharmaceutically acceptable salts thereof.
 65. A compound as recited inclaim 62 wherein R¹ is ethyl; and R² is indazol-5-yl or thepharmaceutically acceptable salts thereof.
 66. A compound as recited inclaim 62 wherein R¹ is ethyl; and R² is benzimidazol-5-yl or thepharmaceutically acceptable salts thereof.
 67. A compound as recited inclaim 62 wherein R¹ is ethyl; and R² is 1-methylbenzimidazol-6-yl or thepharmaceutically acceptable salts thereof.
 68. A compound as recited inclaim 62 wherein R¹ is n-propyl; and R² is 5-quinolinyl or thepharmaceutically acceptable salts thereof.
 69. A compound as recited inclaim 62 wherein R¹ is isopropyl; and R² is 5-quinolinyl or thepharmaceutically acceptable salts thereof.
 70. A compound as recited inclaim 62 wherein R¹ is ethyl; and R is 6-quinolinyl or thepharmaceutically acceptable salts thereof.
 71. A compound as recited inclaim 62 wherein R¹ is ethyl; and R² is 2-methylbenzimidazol-5-yl or thepharmaceutically acceptable salts thereof.
 72. A compound as recited inclaim 62 wherein R¹ is ethyl; and R² is 1,4-benzodioxan-6-yl or thepharmaceutically acceptable salts thereof.
 73. A compound as recited inclaim 62 wherein R¹ is ethyl; and R² is benzotriazol-5-yl or thepharmaceutically acceptable salts thereof.
 74. A compound as recited inclaim 62 wherein R¹ is ethyl; and R² is 3-chloroindazol-5-yl or thepharmaceutically acceptable salts thereof.
 75. A compound as recited inclaim 62 wherein R¹ is butyl; and R² is 5-quinolinyl or thepharmaceutically acceptable salts thereof.
 76. A compound as recited inclaim 62 wherein R¹ is n-propyl; and R² is 6-quinolinyl or thepharmaceutically acceptable salts thereof.
 77. A compound as recited inclaim 62 wherein R¹ is isopropyl; and R² is 6-quinolinyl or thepharmaceutically acceptable salts thereof.
 78. A compound as recited inclaim 1 wherein Z is

R^(1 is (C) ₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl,said (C₁-C₄)alkyl optionally substituted with from one to ninefluorines, said R¹ substituent optionally mono- or di-substitutedindependently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinylor (C₁-C₄)alkylsulfonyl; and R² is a five to six membered nonaromaticheterocyclic ring having one to two heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen or R² is unsubstituted (C₁-C₄)alkyl orunsubstituted (C₃-C₇)cycloalkyl; or R² is phenyl(C₁-C₄)alkyl, or abicyclic ring consisting of two fused five and/or six membered partiallysaturated, fully saturated or fully unsaturated rings takenindependently having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen, said R² substituents optionally substitutedon carbon or nitrogen with up to three substituents independentlyselected from R⁶, R⁷ and R⁸, wherein one of R⁶, R⁷ and R⁸ is optionallya partially saturated, fully saturated, or fully unsaturated three toseven membered ring optionally having one to three heteroatoms selectedindependently from oxygen, sulfur and nitrogen optionally substitutedwith (C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸ are optionally hydroxy,nitro, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl, wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl,(C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylaminoor (C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines; or a pharmaceutically acceptable salt thereof.
 79. Acompound as recited in claim 78 wherein R¹ is (C₁-C₄)alkyl; and R² is abicyclic ring consisting of two fused five and/or six membered partiallysaturated, fully saturated or fully unsaturated rings takenindependently having one to three heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen, said R² bicyclic ring is optionallymono-substituted on carbon or nitrogen with a fully saturated or fullyunsaturated five to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,said ring optionally mono-substituted with (C₁-C₄)alkyl said R² bicyclicring is also optionally mono- or di-substituted independently on carbonor nitrogen with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, (C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— ordi-N,N—(C₁-C₄)alkylamino are optionally mono-substituted with hydroxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tonine fluorines; or a pharmaceutically acceptable salt thereof.
 80. Acompound as recited in claim 79 wherein R² is a quinazolinyl,phthalazinyl, quinolinyl, isoquinolinyl, cinnolinyl, benzodioxanyl,quinoxalinyl, benzopyranyl, benzothiophenyl, benzodioxolyl,benzimidazolyl, indazolyl, indolyl, benzotriazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl orbenzothiadiazolyl ring, wherein said R² bicyclic ring is optionallymono- or di-substituted independently with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, mono-N— or di-N,N—(C₁-C₄)alkylamino substituents areoptionally mono-substituted with hydroxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto five fluorines; or a pharmaceutically acceptable salt thereof.
 81. Acompound as recited in claim 1 wherein the compound is[1-(indazol-7-yl)-3-methyl-1H-pyrazole-4-carbonyl]guanidine;[1-(2,1,3-benzothiadiazol-4-yl)-3-methyl-1H-pyrazole-4-carbonyl]guanidine;[3-methyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine; or apharmaceutically acceptable salt thereof.
 82. A compound as recited inclaim 80 wherein R¹ is methyl; and R² is indazol-7-yl or apharmaceutically acceptable salt thereof.
 83. A compound as recited inclaim 80 wherein R¹ is methyl; and R² is 2,1,3-benzothiadiazol-4-yl or apharmaceutically acceptable salt thereof.
 84. A compound as recited inclaim 80 wherein R¹ is methyl; and R² is quinolin-5-yl or apharmaceutically acceptable salt thereof.
 85. A compound as recited inclaim 1 wherein Z is

R⁴ is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl or phenyl(C₁-C₄)alkyl,said (C₁-C₄)alkyl optionally substituted with from one to ninefluorines, said R⁴ substituent optionally mono- or di-substitutedindependently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinylor (C₁-C₄)alkylsulfonyl; and R⁵ is a five to six membered nonaromaticheterocyclic ring having one to two heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen or R⁵ is unsubstituted (C₁-C₄)alkyl orunsubstituted (C₃-C₇)cycloalkyl; or R⁵ is phenyl(C₁-C₄)alkyl, or abicyclic ring consisting of two fused five and/or six membered partiallysaturated, fully saturated or fully unsaturated rings takenindependently having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen, said R⁵ substituents optionally substitutedon carbon or nitrogen with up to three substituents independentlyselected from R⁶, R⁷ and R⁸, wherein one of R⁶, R⁷ and R⁸ is optionallya partially saturated, fully saturated, or fully unsaturated three toseven membered ring optionally having one to three heteroatoms selectedindependently from oxygen, sulfur and nitrogen optionally substitutedwith (C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸ are optionally hydroxy,nitro, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl, wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl,(C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylaminoor (C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines; or a pharmaceutically acceptable salt thereof.
 86. Acompound as recited in claim 85 wherein R⁴ (C₁-C₄)alkyl; and R⁵ is abicyclic ring consisting of two fused five and/or six membered partiallysaturated, fully saturated or fully unsaturated rings takenindependently having one to three heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen, said R⁵ bicyclic ring is optionallymono-substituted on carbon with a fully saturated or fully unsaturatedfive to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen, said ringoptionally mono-substituted with (C₁-C₄)alkyl, said R⁵ bicyclic ring isalso optionally mono- or di-substituted independently on carbon ornitrogen with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, (C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— ordi-N,N—(C₁-C₄)alkylamino are optionally mono-substituted with hydroxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tonine fluorines; or a pharmaceutically acceptable salt thereof.
 87. Acompound as recited in claim 86 wherein R₅ is a quinazolinyl,phthalazinyl, quinolinyl, isoquinolinyl, cinnolinyl, benzodioxanyl,quinoxalinyl, benzopyranyl, benzothiophenyl, benzodioxolyl,benzimidazolyl, indazolyl, indolyl, benzotriazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl orbenzothiadiazolyl ring, wherein said R⁵ bicyclic ring is optionallymono- or di-substituted independently with hydroxy, halo, (C₁-C₄)alkoxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, mono-N— or di-N,N—(C₁-C₄)alkylamino substituents areoptionally mono-substituted with hydroxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto five fluorines; or a pharmaceutically acceptable salt thereof.
 88. Amethod of preventing myocardial ischemic damage comprising the chronicoral administration to a human in need of such treatment of atherapeutically effective amount of a compound a prodrug of saidcompound as recited in claim 1 or a pharmaceutically acceptable salt ofsaid compound or of said prodrug.
 89. A compound as recited in claim 1wherein Z is

R² is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, M or M(C₁-C₄)alkyl, any of saidprevious (C₁-C₄)alkyl moieties optionally having from one to ninefluorines; said (C₁-C₄)alkyl or (C₃-C₄)cycloalkyl optionally mono- ordi-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,(C₁-C₄)alkyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl; and said (C₃-C₄)cycloalkyl optionallyhaving from one to seven fluorines; wherein M is a partially saturated,fully saturated or fully unsaturated five to eight membered ringoptionally having one to three heteroatoms selected independently fromoxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated three to sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen;said M is optionally substituted, on one ring if the moiety ismonocyclic, or one or both rings if the moiety is bicyclic, on carbon ornitrogen with up to three substituents independently selected from R⁶,R⁷ and R⁸, wherein one of R⁶, R⁷ and R⁸ is optionally a partiallysaturated, fully saturated, or fully unsaturated three to seven memberedring optionally having one to three heteroatoms selected independentlyfrom oxygen, sulfur and nitrogen optionally substituted with(C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸ are optionally hydroxy,nitro, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl, wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl,(C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— or di-N,N—(C₁-C₄)alkylaminoor (C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸ substituents are optionallymono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N—or di-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines; and R³ is (C₁-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl orphenyl(C₁-C₄)alkyl, said (C₁-C₄)alkyl optionally substituted with fromone to nine fluorines, said R³ substituent optionally mono- ordi-substituted independently with (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or (C₁-C₄)alkyl, or apharmaceutically acceptable salt thereof.
 90. A compound as recited inclaim 89 wherein R³ is (C₁-C₄)alkyl; R² is phenyl, said phenyloptionally mono-substituted on carbon with a fully saturated or fullyunsaturated five to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,said ring optionally mono-substituted with (C₁-C₄)alkyl, said R² ring isalso optionally mono- or di-substituted independently on carbon withhydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl, wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, (C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— ordi-N,N—(C₁-C₄)alkylamino are optionally mono-substituted with hydroxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tonine fluorines; or a pharmaceutically acceptable salt thereof.
 91. Acompound as recited in claim 89 wherein R³ is (C₁-C₄)alkyl; R² is abicyclic ring consisting of two fused five and/or six membered partiallysaturated, fully saturated or fully unsaturated rings takenindependently said R² bicyclic ring is optionally mono-substituted oncarbon with a fully saturated or fully unsaturated five to six memberedring optionally having one to two heteroatoms selected independentlyfrom oxygen, sulfur and nitrogen, said ring optionally mono-substitutedwith (C₁-C₄)alkyl said R² bicyclic ring is also optionally mono- ordi-substituted independently on carbon with hydroxy, halo,(C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, (C₁-C₄)alkanoyl,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino, (C₁-C₄)alkoxycarbonylamino,sulfonamido, (C₁-C₄)alkylsulfonamido, amino, mono-N— ordi-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, (C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— ordi-N,N—(C₁-C₄)alkylamino are optionally mono-substituted with hydroxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tonine fluorines; or a pharmaceutically acceptable salt thereof.
 92. Acompound as recited in claim 89 wherein R³ is (C₁-C₄)alkyl; R² is a fiveto six membered monocyclic aromatic ring having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen; said R² ring isoptionally mono-substituted on carbon with a fully saturated or fullyunsaturated five to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,said ring optionally mono-substituted with (C₁-C₄)alkyl said R² ring isalso optionally mono- or di-substituted independently on carbon ornitrogen with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, (C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— ordi-N,N—(C₁-C₄)alkylamino are optionally mono-substituted with hydroxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tonine fluorines or a pharmaceutically acceptable salt thereof.
 93. Acompound as recited in claim 89 wherein R³ is (C₁-C₄)alkyl; R² is abicyclic ring consisting of two fused five and/or six membered partiallysaturated, fully saturated or fully unsaturated rings takenindependently having one to three heteroatoms selected independentlyfrom nitrogen, sulfur and oxygen, said R² bicyclic ring is optionallymono-substituted on carbon or nitrogen with a fully saturated or fullyunsaturated five to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,said ring optionally mono-substituted with (C₁-C₄)alkyl said R² bicyclicring is also optionally mono- or di-substituted independently on carbonor nitrogen with hydroxy, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl,(C₁-C₄)alkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, carbamoyl, mono-N— ordi-N,N—(C₁-C₄)alkylcarbamoyl, cyano, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl wherein said (C₁-C₄)alkoxy,(C₁-C₄)alkyl, (C₁-C₇)alkanoyl, (C₁-C₄)alkylthio, mono-N— ordi-N,N—(C₁-C₄)alkylamino are optionally mono-substituted with hydroxy,(C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, mono-N— or di-N,N—(C₁-C₄)alkylcarbamoyl, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N— ordi-N,N—(C₁-C₄)alkylaminosulfonyl or optionally substituted with one tonine fluorines; or a pharmaceutically acceptable salt thereof.
 94. Apharmaceutical combination composition comprising: a therapeuticallyeffective amount of a composition comprising a first compound, saidfirst compound being a compound of claim 1, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug; asecond compound, said second compound being an aldose reductaseinhibitor; and a pharmaceutical carrier, vehicle or diluent.
 95. Apharmaceutical composition as recited in claim 94 wherein the aldosereductase inhibitor is 1-phthalazineacetic acid,3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]- or apharmaceutically acceptable salt thereof.
 96. A pharmaceuticalcombination composition comprising: a therapeutically effective amountof a composition comprising a first compound, said first compound beinga compound of claim 43, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug; a second compound,said second compound being an aldose reductase inhibitor; and apharmaceutical carrier, vehicle or diluent.
 97. A method of reducingtissue damage resulting from ischemia comprising administering to amammal in need of such treatment an amount of a first compound, saidfirst compound being a compound of claim 1, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug; anamount of a second compound, said second compound being an aldosereductase inhibitor; wherein the amounts of the first and secondcompounds result in a therapeutic effect.
 98. A method of reducingtissue damage resulting from ischemia as recited in claim 97 wherein thealdose reductase inhibitor is 1-phthalazineacetic acid,3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]- or apharmaceutically acceptable salt thereof.
 99. A method of reducingtissue damage resulting from ischemia comprising administering to amammal in need of such treatment an amount of a first compound, saidfirst compound being a compound of claim 43, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug; anamount of a second compound, said second compound being an aldosereductase inhibitor; wherein the amounts of the first and secondcompounds result in a therapeutic effect.
 100. A kit comprising: a. afirst compound, said first compound being a compound of claim 1, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug and a pharmaceutically acceptable carrier, vehicle ordiluent in a first unit dosage form; b. a second compound, said secondcompound being an aldose reductase inhibitor and a pharmaceuticallyacceptable carrier, vehicle or diluent in a second unit dosage form; andc. means for containing said first and second dosage forms wherein theamounts of first and second compounds result in a therapeutic effect.101. A kit as recited in claim 100 wherein the aldose reductaseinhibitor is 1-phthalazineacetic acid,3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]- or apharmaceutically acceptable salt thereof.
 102. A kit comprising: a. afirst compound, said first compound being a compound of claim 43, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug and a pharmaceutically acceptable carrier, vehicle ordiluent in a first unit dosage form; b. a second compound, said secondcompound being an aldose reductase inhibitor and a pharmaceuticallyacceptable carrier, vehicle or diluent in a second unit dosage form; andc. means for containing said first and second dosage forms wherein theamounts of first and second compounds result in a therapeutic effect.103. A pharmaceutical combination composition comprising: atherapeutically effective amount of a composition comprising a firstcompound, said first compound being a compound of claim 1, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug; a second compound, said second compound being a glycogenphosphorylase inhibitor; and a pharmaceutical carrier, vehicle ordiluent.
 104. A pharmaceutical composition as recited in claim 103wherein the glycogen phosphorylase inhibitor is5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3S)-hydroxypyrrolidin-1-yl)-3-oxopropyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((3S,4S)-dihydroxypyrrolidin-1-yl)-(2R)-hydroxy-3-oxopropyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-((R)-hydroxy-dimethylcarbamoylmethyl)-2-phenyl-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-((R)-hydroxy-methoxy-methylcarbamoyl)-methyl)-2-phenyl-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-((R)-hydroxy-[(2-hydroxy-ethyl)-methylcarbamoyl]-methyl)-2-phenyl-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxyimino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((cis)-dihydroxypyrrolidin-1-yl)-(2R)-hydroxy-3-oxopropyl]-amide;5-chloro-1H-indole-2-carboxylic acid[2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]amide;5-chloro-1H-indole-2-carboxylic acid[2-(1,1-dioxo-thiazolidin-3-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-(4-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-((3RS)-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[2-oxo-2-((1RS)-oxo-thiazolidin-3-yl)-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide; orpharmaceutically acceptable salt thereof.
 105. A pharmaceuticalcombination composition comprising: a therapeutically effective amountof a composition comprising a first compound, said first compound beinga compound of claim 43, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug; a second compound,said second compound being a glycogen phosphorylase inhibitor; and apharmaceutical carrier, vehicle or diluent.
 106. A method of reducingtissue damage resulting from ischemia comprising administering to amammal in need of such treatment an amount of a first compound, saidfirst compound being a compound of claim 1, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug;and an amount of a second compound, said second compound being aglycogen phosphorylase inhibitor; wherein the amounts of first andsecond compounds result in a therapeutic effect.
 107. A method ofreducing tissue damage resulting from ischemia as recited in claim 106wherein the glycogen phosphorylase inhibitor is5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3S)-hydroxypyrrolidin-1-yl)-3-oxopropyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((3S,4S)-dihydroxypyrrolidin-1-yl)-(2R)-hydroxy-3-oxopropyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-((R)-hydroxy-dimethylcarbamoylmethyl)-2-phenyl-ethyl]-amide,5-chloro-1H-indole-2-carboxylic acid[(1S)-((R)-hydroxy-methoxy-methylcarbamoyl)-methyl)-2-phenyl-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-((R)-hydroxy-[(2-hydroxy-ethyl)-methylcarbamoyl]-methyl)-2-phenyl-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxyimino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((cis)-dihydroxypyrrolidin-1-yl)-(2R)-hydroxy-3-oxopropyl]-amide;5-chloro-1H-indole-2-carboxylic acid[2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[2-(1,1-dioxo-thiazolidin-3-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-(4-fluoro-benzyl)-2-(4-hydroxy-piperidin-1yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-((3RS)-hydroxy-piperidin-1-yl-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[2-oxo-2-((1RS)-oxo-thiazolidin-3-yl)-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide; or apharmaceutically acceptable salt thereof.
 108. A method of reducingtissue damage resulting from ischemia comprising administering to amammal in need of such treatment an amount of a first compound, saidfirst compound being a compound of claim 43, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug;and an amount of a second compound, said second compound being aglycogen phosphorylase inhibitor; wherein the amounts of first andsecond compounds result in a therapeutic effect.
 109. A kit comprising:a. a first compound, said first compound being a compound of claim 1, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug and a pharmaceutically acceptable carder, vehicle ordiluent in a first unit dosage form; b. a second compound, said secondcompound being an glycogen phosphorylase inhibitor and apharmaceutically acceptable carrier, vehicle or diluent in a second unitdosage form; and c. means for containing said first and second dosageforms herein the amounts of first and second compounds result in atherapeutic effect.
 110. A kit as recited in claim 109 wherein theglycogen phosphorylase inhibitor is 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3S)-hydroxypyrrolidin-1-yl)-3-oxopropyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((3S,4S)-dihydroxypyrrolidin-1-yl)-(2R)-hydroxy-3-oxopropyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-((R)-hydroxy-dimethylcarbamoyl-methyl)-2-phenyl-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-((R)-hydroxy-methoxy-methylcarbamoyl)-methyl)-2-phenyl-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-((R)-hydroxy-[(2-hydroxy-ethyl)-methylcarbamoyl]-methyl)-2-phenyl-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxyimino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((cis)-dihydroxypyrrolidin-1-yl)-(2R)-hydroxy-3-oxopropyl]-amide;5-chloro-1H-indole-2-carboxylic acid[2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[2-(1,1-dioxo-thiazolidin-3-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-(4-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-((3RS)-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[2-oxo-2-((1RS)-oxo-thiazolidin-3-yl)-ethyl]-amide;5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2y -oxo-ethyl]-amide; or apharmaceutically acceptable salt thereof.
 111. A kit comprising: a. afirst compound, said first compound being a compound of claim 43, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug and a pharmaceutically acceptable carrier, vehicle ordiluent in a first unit dosage form; b. a second compound, said secondcompound being an glycogen phosphorylase inhibitor and apharmaceutically acceptable carrier, vehicle or diluent in a second unitdosage form; and c. means for containing said first and second dosageforms wherein the amounts of first and second compounds result in atherapeutic effect.
 112. A pharmaceutical combination compositioncomprising: a therapeutically effective amount of a compositioncomprising a first compound, said first compound being a compound ofclaim 1, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug; a second compound, said secondcompound being a cardiovascular agent; and a pharmaceutical carrier,vehicle or diluent.
 113. A pharmaceutical composition as recited inclaim 70 wherein the cardiovascular agent is a β-blocker, a calciumchannel blocker, a potassium channel opener, adenosine, adenosineagonists, an ACE inhibitor, a nitrate, a diuretic, a glycoside, athrombolytic, a platelet inhibitor, aspirin, dipyridamol, potassiumchloride, clonidine, prazosin or an adenosine A₃ receptor agonist. 114.A pharmaceutical combination composition comprising: a therapeuticallyeffective amount of a composition comprising a first compound, saidfirst compound being a compound of claim 43, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug; asecond compound, said second compound being a cardiovascular agent; anda pharmaceutical carrier, vehicle or diluent.
 115. A method of reducingtissue damage resulting from ischemia comprising administering to amammal in need of such treatment an amount of a first compound, saidfirst compound being a compound of claim 1, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug; anamount of a second compound, said second compound being a cardiovascularagent; wherein the amounts the of first and second compounds result in atherapeutic effect.
 116. A method of reducing tissue damage resultingfrom ischemia as recited in claim 73 wherein the cardiovascular agent isa β-blocker, a potassium channel opener, adenosine, adenosine agonists,a calcium channel blocker, an ACE inhibitor, a nitrate, a diuretic, aglycoside, a thrombolytic, a platelet inhibitor, aspirin, dipyridamol,potassium chloride, clonidine, prazosin or an adenosine A₃ receptoragonist.
 117. An method of reducing tissue damage resulting fromischemia comprising administering to a mammal in need of such treatmentan amount of a first compound, said first compound being a compound ofclaim 42, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug; an amount of a second compound, saidsecond compound being a cardiovascular agent; wherein the amounts the offirst and second compounds result in a therapeutic effect.
 118. A kitcomprising: a. a first compound, said first compound being a compound ofclaim 1, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug and a pharmaceutically acceptablecarrier, vehicle or diluent in a first unit dosage form; b. a secondcompound, said second compound being a cardiovascular agent and apharmaceutically acceptable carrier, vehicle or diluent in a second unitdosage form; and c. means for containing said first and second dosageforms wherein the amounts of theist and second compounds result in atherapeutic effect.
 119. A kit as recited in claim 118 wherein thecardiovascular agent is a β-blocker, a calcium channel blocker, an ACEinhibitor, a nitrate, a diuretic, a glycoside, a thrombolytic, aplatelet inhibitor, aspirin, dipyridamol, potassium chloride, clonidine,prazosin or an adenosine A₃ receptor agonist.
 120. A kit comprising: a.a first compound, said first compound being a compound of claim 43, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug and a pharmaceutically acceptable carrier, vehicle ordiluent in a first unit dosage form; b. a second compound, said secondcompound being a cardiovascular agent and a pharmaceutically acceptablecarrier, vehicle or diluent in a second unit dosage form; and c. meansfor containing said first and second dosage forms wherein the amounts ofthe first and second compounds result in a therapeutic effect.
 121. Acompound which is[5-methyl-1-(quinolin-6-yl)-1H-pyrazole-4-carbonyl]guanidine;[5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine; or[5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidine or thepharmaceutically acceptable salts thereof.
 122. A compound as recited inclaim 1 wherein the compound is[3methyl-1-(isoquinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine or thepharmaceutically acceptable salts thereof.
 123. A compound as recited inclaim 1 wherein the compound is[2-(isoquinolin-5-yl)-5-methyl-2H-1,2,3-triazole-4-carbonyl]guanidine;or [5methyl-2-(quinolin-5-yl)-2H-1,2,3-triazole-4-carbonyl]guanidine orthe pharmaceutically acceptable salts thereof.
 124. A method of reducingtissue damage resulting from ischemia comprising administering to amammal in need of such treatment a therapeutically effective amount of[5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine or apharmaceutically acceptable salt thereof.
 125. A method as recited inclaim 124 wherein the mammal is a human and the compound is administeredprior to, during and after surgery and the tissue is heart tissue. 126.A method as recited in claim 125 wherein the therapeutically effectiveamount is 0.01 mg/kg/day to about 50 mg/kg/day and the compound isadministered intravenously.
 127. A method as recited in claim 126wherein the pharmaceutically acceptable salt is the monomesylate salt.128. A method as recited in claim 124 the mammal is a human, thecompound is administered prior to, during or subsequent to surgery andthe tissue is heart tissue.
 129. A pharmaceutical composition whichcomprises a therapeutically effective amount of[5-cyclopropyl-1-(quinolin-5yl)-1H-pyrazole-4-carbonyl]guanidine or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable vehicle, diluent or carrier.
 130. A pharmaceuticalcomposition as recited in claim 129 wherein the therapeuticallyeffective amount is 0.01 mg/kg/day to about 50 mg/kg/day and thecomposition is intravenous.
 131. A pharmaceutical composition as recitedin claim 130 wherein the pharmaceutically acceptable salt is themonomesylate salt. 132.[5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidinemonomesylate.